rs4664475

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001164508.2(NEB):c.21585A>G(p.Thr7195=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,611,460 control chromosomes in the GnomAD database, including 297,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24444 hom., cov: 31)

Exomes 𝑓: 0.61 ( 273354 hom. )

Consequence

NEB
NM_001164508.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -3.29

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-151531039-T-C is Benign according to our data. Variant chr2-151531039-T-C is described in ClinVar as [Benign]. Clinvar id is 95114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151531039-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.29 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.21585A>G	p.Thr7195=	synonymous_variant	145/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.21585A>G	p.Thr7195=	synonymous_variant	145/182	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.21585A>G	p.Thr7195=	synonymous_variant	145/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.21585A>G	p.Thr7195=	synonymous_variant	145/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3

Frequencies

GnomAD3 genomes

AF:

0.555

AC:

84284

AN:

151820

Hom.:

24422

Cov.:

show subpopulations

Gnomad AFR

AF:

0.389

Gnomad AMI

AF:

0.509

Gnomad AMR

AF:

0.681

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.582

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.644

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.625

Gnomad OTH

AF:

0.565

GnomAD3 exomes

AF:

0.589

AC:

145970

AN:

247906

Hom.:

44307

AF XY:

0.579

AC XY:

77812

AN XY:

134422

show subpopulations

Gnomad AFR exome

AF:

0.389

Gnomad AMR exome

AF:

0.724

Gnomad ASJ exome

AF:

0.523

Gnomad EAS exome

AF:

0.578

Gnomad SAS exome

AF:

0.409

Gnomad FIN exome

AF:

0.639

Gnomad NFE exome

AF:

0.620

Gnomad OTH exome

AF:

0.610

GnomAD4 exome

AF:

0.608

AC:

886922

AN:

1459522

Hom.:

273354

Cov.:

AF XY:

0.601

AC XY:

436676

AN XY:

726030

show subpopulations

Gnomad4 AFR exome

AF:

0.387

Gnomad4 AMR exome

AF:

0.716

Gnomad4 ASJ exome

AF:

0.520

Gnomad4 EAS exome

AF:

0.626

Gnomad4 SAS exome

AF:

0.410

Gnomad4 FIN exome

AF:

0.641

Gnomad4 NFE exome

AF:

0.626

Gnomad4 OTH exome

AF:

0.590

GnomAD4 genome

AF:

0.555

AC:

84339

AN:

151938

Hom.:

24444

Cov.:

AF XY:

0.557

AC XY:

41374

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.390

Gnomad4 AMR

AF:

0.682

Gnomad4 ASJ

AF:

0.510

Gnomad4 EAS

AF:

0.582

Gnomad4 SAS

AF:

0.404

Gnomad4 FIN

AF:

0.644

Gnomad4 NFE

AF:

0.625

Gnomad4 OTH

AF:

0.558

Alfa

AF:

0.604

Hom.:

35137

Bravo

AF:

0.556

Asia WGS

AF:

0.451

AC:

1572

AN:

3478

EpiCase

AF:

0.602

EpiControl

AF:

0.612

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	This is a RefSeq error. The reference base (c.21690A) is the minor allele. This allele (A) has been identified in 38% (3158/8354) of European American chromosom es and 59% (2374/4046) of African American chromosomes by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs4664475) and thus meets criteria to be classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Nemaline myopathy 2

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: The NEB c.21690A>G (p.Thr7230Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 69172/118646 control chromosomes (20606 homozygotes) at a frequency of 0.5830116, which is approximately 165 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence that this variant is a benign polymorphism. Multiple clinical diagnostic laboratories cite the variant as "benign." Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Arthrogryposis multiplex congenita 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.094

DANN

Benign

0.53

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