rs761232641

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PP4PM3_StrongPP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.22144A>C p.(Thr7382Pro) variant in NEB is a missense variant predicted to cause substitution of Threonine by Proline at amino acid 7382. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001406 (9/64028 alleles) in the Finnish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a SCORE of 0.286 which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. This variant has been detected in 4 individuals with typical nemaline myopathy. Two of those individuals were compound heterozygous with an LP/P variant, phase confirmed and two were homozygous (PMID:16917880, 17525139) (PM3_Strong). At least two individuals with this variant displayed nemaline bodies (confirmed by electron microscopy), which is highly specific for nemaline myopathy (PP4, PMID:17525139). The variant has been reported to segregate with nemaline myopathy in 3 individuals with biallelic occurrence and 5 unaffected family members did not have biallelic occurrence in 2 families (PP1_Strong; PMID:17525139). Binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays (PMID:25110572) showed weaker binding than WT proteins to tropomyosin. However, this assay does not meet the requirements for use by the ClinGen Congenital Myopathies VCEP. In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM3_Strong, PP1_Strong, PP4. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1906766/MONDO:0018958/146

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 3.29

Publications

2 publications found

Variant links:

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

NEB links:

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RIF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 9 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.22144A>C	p.Thr7382Pro	missense_variant	Exon 150 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.22144A>C	p.Thr7382Pro	missense_variant	Exon 150 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.22144A>C	p.Thr7382Pro	missense_variant	Exon 150 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.22144A>C	p.Thr7382Pro	missense_variant	Exon 150 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249100

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111746

Other (OTH)

AF:

0.0000166

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68050

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000325

Hom.:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Nemaline myopathy

Pathogenic:2

Mar 03, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Thr7382Pro variant in NEB has been reported at least 8 individuals with nemaline myopathy (PMID: 12207938, 16917880, 17525139), segregated with disease in seven affected relatives from three families (PMID: 12207938, 17525139), and has been identified in 0.01% (9/64028) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs761232641). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 506284) and has been interpreted as pathogenic by Invitae and OMIM. Of the affected individuals, two of those were homozygotes and two were compound heterozygotes that carried reported likely pathogenic variants in trans, which increases the likelihood that the p.Thr7382Pro variant is pathogenic (PMID: 12207938, 16917880, 17525139). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual heterozygous for this variant is highly specific for nemaline myopathy based on the presence of nemaline rods consistent with disease (PMID: 17525139). ACMG/AMP Criteria applied: PP1_strong, PM3_strong, PP4, PM2_supporting (Richards 2015). -

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.22144A>C p.(Thr7382Pro) variant in NEB is a missense variant predicted to cause substitution of Threonine by Proline at amino acid 7382. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001406 (9/64028 alleles) in the Finnish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a SCORE of 0.286 which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. This variant has been detected in 4 individuals with typical nemaline myopathy. Two of those individuals were compound heterozygous with an LP/P variant, phase confirmed and two were homozygous (PMID:16917880, 17525139) (PM3_Strong). At least two individuals with this variant displayed nemaline bodies (confirmed by electron microscopy), which is highly specific for nemaline myopathy (PP4, PMID:17525139). The variant has been reported to segregate with nemaline myopathy in 3 individuals with biallelic occurrence and 5 unaffected family members did not have biallelic occurrence in 2 families (PP1_Strong; PMID:17525139). Binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays (PMID: 25110572) showed weaker binding than WT proteins to tropomyosin. However, this assay does not meet the requirements for use by the ClinGen Congenital Myopathies VCEP. In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM3_Strong, PP1_Strong, PP4. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) -

Nemaline myopathy 2

Pathogenic:2

Jul 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects NEB protein function (PMID: 25110572). This sequence change replaces threonine with proline at codon 7417 of the NEB protein (p.Thr7417Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs761232641, ExAC 0.02%). This variant has been observed in individual(s) with autosomal recessive NEB-related conditions (PMID: 16917880, 17525139). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr5681Pro, g. 207181A>C (p.Thr5681Pro), and c.22144A>C (p.Thr7382Pro). ClinVar contains an entry for this variant (Variation ID: 506284). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). -

Apr 03, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

.;.;T;.;T;T;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.49

T;T;T;T;T;T;.;.

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.0

M;.;.;.;M;.;.;.

PhyloP100

3.3

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.9

D;D;.;N;D;D;.;.

REVEL

Benign

0.29

Sift

Benign

0.034

D;D;.;D;D;D;.;.

Sift4G

Uncertain

0.0040

D;D;D;D;D;T;D;D

Polyphen

1.0

.;.;.;.;D;.;.;.

Vest4

0.63

MutPred

0.85

Gain of ubiquitination at K5678 (P = 0.0626);.;.;.;Gain of ubiquitination at K5678 (P = 0.0626);.;.;.;

MVP

0.56

MPC

0.38

ClinPred

0.83

GERP RS

6.1

Varity_R

0.77

gMVP

0.50

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over