Variant rs750039342 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001164508.2(NEB):c.21337A>T(p.Met7113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.06

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:):

RIF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14229718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164508.2 linkuse as main transcript	c.21337A>T	p.Met7113Leu	missense_variant	143/182	ENST00000397345.8	NP_001157980.2
NEB	NM_001164507.2 linkuse as main transcript	c.21417+693A>T		intron_variant		ENST00000427231.7	NP_001157979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.21337A>T	p.Met7113Leu	missense_variant	143/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.21417+693A>T		intron_variant		5	NM_001164507.2	ENSP00000416578	A2	P20929-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000639

AC:

AN:

156432

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689942

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.0094

T;.;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.45

T;T;.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;D;N

PROVEAN

Benign

-0.82

.;N;.;N

REVEL

Benign

0.11

Sift

Benign

0.16

.;T;.;T

Sift4G

Benign

0.15

T;T;T;.

Vest4

0.34

MutPred

0.46

.;Loss of catalytic residue at M7113 (P = 0.0241);Loss of catalytic residue at M7113 (P = 0.0241);.;

MVP

0.30

MPC

0.050

ClinPred

0.22

GERP RS

6.2

gMVP

0.047

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: 24

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over