rs143473183

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001164508.2(NEB):c.9181A>T(p.Met3061Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,613,996 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: -0.0960

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013075799).

BP6

Variant 2-151633887-T-A is Benign according to our data. Variant chr2-151633887-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 450097.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00149 (227/152292) while in subpopulation AFR AF= 0.0052 (216/41562). AF 95% confidence interval is 0.00463. There are 1 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.9181A>T	p.Met3061Leu	missense_variant	65/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.9181A>T	p.Met3061Leu	missense_variant	65/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.9181A>T	p.Met3061Leu	missense_variant	65/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.9181A>T	p.Met3061Leu	missense_variant	65/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.8854-2709A>T		intron_variant		5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00495

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000341

AC:

AN:

249256

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

135218

show subpopulations

Gnomad AFR exome

AF:

0.00471

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000143

AC:

209

AN:

1461704

Hom.:

Cov.:

115

AF XY:

0.000132

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00493

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.00149

AC:

227

AN:

152292

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

121

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00520

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000812

Hom.:

Bravo

AF:

0.00145

ESP6500AA

AF:

0.00361

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000389

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 07, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 20, 2018	- -

Nemaline myopathy 2

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -

NEB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2020

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

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.023

.;T;.;.;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.80

T;T;T;.;.

M_CAP

Benign

0.017

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;N;N

PROVEAN

Benign

-0.98

N;.;N;.;.

REVEL

Benign

0.087

Sift

Benign

0.090

T;.;T;.;.

Sift4G

Uncertain

0.019

D;D;D;D;D

Vest4

0.29

MutPred

0.48

Loss of catalytic residue at M3061 (P = 0.0109);Loss of catalytic residue at M3061 (P = 0.0109);Loss of catalytic residue at M3061 (P = 0.0109);Loss of catalytic residue at M3061 (P = 0.0109);Loss of catalytic residue at M3061 (P = 0.0109);

MVP

0.36

MPC

0.050

ClinPred

0.041

GERP RS

6.0

gMVP

0.019

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over