rs78592085

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001164507.2(NEB):c.25367C>T(p.Thr8456Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,612,568 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T8456T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 7 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:7

Conservation

PhyloP100: 9.01

Publications

9 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011208594).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00203 (309/152250) while in subpopulation AMR AF = 0.00543 (83/15298). AF 95% confidence interval is 0.00448. There are 3 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.25367C>T	p.Thr8456Met	missense_variant	Exon 181 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.25367C>T	p.Thr8456Met	missense_variant	Exon 181 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.25367C>T	p.Thr8456Met	missense_variant	Exon 181 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.25367C>T	p.Thr8456Met	missense_variant	Exon 181 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

311

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00262

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00196

AC:

489

AN:

248872

AF XY:

0.00186

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.00385

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00262

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00255

AC:

3725

AN:

1460318

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

1803

AN XY:

726530

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33450

American (AMR)

AF:

0.00400

AC:

179

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26130

East Asian (EAS)

AF:

0.00116

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00294

AC:

3260

AN:

1110632

Other (OTH)

AF:

0.00227

AC:

137

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

171

342

513

684

855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00203

AC:

309

AN:

152250

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41548

American (AMR)

AF:

0.00543

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00262

AC:

178

AN:

68006

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00258

Hom.:

Bravo

AF:

0.00286

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000532

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00176

AC:

213

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Nov 20, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1 -

Nemaline myopathy 2

Uncertain:2Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. -

not specified

Uncertain:2

Jul 01, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The T8491M variants in the NEB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. While not present in the homozygous state, the NHLBI Exome Sequencing Project reports T8491M was observed in 22/8232 (0.3%) alleles from individuals of European American background and the 1000 Genomes Project reports this variant was observed in 2/214 (0.9%) alleles from individuals of Italian ancestry, indicating it may be a rare variant in these populations. The T8491M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T8491M as a variant of uncertain significance. -

Muscle weakness;C0699743:Congenital muscular dystrophy

Uncertain:1

May 21, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEB-related disorder

Benign:1

Jun 05, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.059

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

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

T;D;T;D;T;T;.;.

M_CAP

Benign

0.049

MetaRNN

Benign

0.011

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.8

L;.;.;.;L;.;.;.

PhyloP100

9.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.6

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

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.071

.;.;.;.;B;.;.;.

Vest4

0.54

MVP

0.47

MPC

0.34

ClinPred

0.035

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.39

Mutation Taster

=94/6

polymorphism

(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