rs767584361

chr2-151526204-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001164507.2(NEB):c.22004C>T(p.Thr7335Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T7335T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.04

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]

RIF1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-151526204-G-A is Benign according to our data. Variant chr2-151526204-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 452689.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.22004C>T	p.Thr7335Met	missense_variant	149/182	ENST00000427231.7
NEB	NM_001164508.2	c.22004C>T	p.Thr7335Met	missense_variant	149/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.22004C>T	p.Thr7335Met	missense_variant	149/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.22004C>T	p.Thr7335Met	missense_variant	149/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000113 AC: 28 AN: 248754 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 134932

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461602 Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74352

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2017

The T7370M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T7370M variant is observed in 10/30,758 (0.03%) alleles from individuals of South Asian background (Lek et al., 2016). This 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. However, most reported pathogenic variants in the NEB gene are truncating/loss-of-function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;D;D;D;T;D;.;.
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	2.9	M;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;D;.;D;D;D;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;D;.;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.;.
Vest4		0.83
MVP		0.68
MPC		0.35
ClinPred		0.70	D
GERP RS		6.1
Varity_R		0.26
gMVP		0.55

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

Other links and lift over

dbSNP: rs767584361; hg19: chr2-152382718; COSMIC: COSV50857518; COSMIC: COSV50857518;