NM_000260.4:c.2527G>A

Variant names:

• chr11-77179894-G-A
• rs140559111
• NM_000260.4:c.2527G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The c.2527G>A variant in MYO7A is a missense variant predicted to cause substitution of valine by methionine at amino acid 843. The variant is present in 0.0006965 (23/22568) of South Asian alleles with a confidence interval of 95% in gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.25, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function. The variant has been reported in 6 probands, all of whom did not have clinical/phenotypic data, had other potentially pathogenic variants, or did not present with hearing loss (PMID:30755392, GeneDx, EGL Eurofins, Illumina). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the absence of ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132253/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:14 B:2
• Conservation: PhyloP100: 0.565
• Publications: 5 publications found

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

MYO7A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.2527G>A	p.Val843Met	missense	Exon 21 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.2527G>A	p.Val843Met	missense	Exon 21 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.2494G>A	p.Val832Met	missense	Exon 22 of 50	NP_001356294.1	Q13402-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.2527G>A	p.Val843Met	missense	Exon 21 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.2527G>A	p.Val843Met	missense	Exon 21 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.2494G>A	p.Val832Met	missense	Exon 22 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152248 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000456 AC: 63 AN: 138042 AF XY: 0.000534

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000229

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.000334 AC: 463 AN: 1387352 Hom.: 1 Cov.: 31 AF XY: 0.000364 AC XY: 249 AN XY: 684544

African (AFR) AF: 0.000127 AC: 4 AN: 31552

American (AMR) AF: 0.000477 AC: 17 AN: 35672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35690

South Asian (SAS) AF: 0.000847 AC: 67 AN: 79114

European-Finnish (FIN) AF: 0.000610 AC: 24 AN: 39344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4746

European-Non Finnish (NFE) AF: 0.000294 AC: 317 AN: 1078300

Other (OTH) AF: 0.000571 AC: 33 AN: 57774

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152366 Hom.: 0 Cov.: 34 AF XY: 0.000295 AC XY: 22 AN XY: 74500

African (AFR) AF: 0.0000962 AC: 4 AN: 41588

American (AMR) AF: 0.000131 AC: 2 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000516 Hom.: 1

Bravo AF: 0.000253

ESP6500AA AF: 0.000277 AC: 1

ESP6500EA AF: 0.000282 AC: 2

ExAC AF: 0.000337 AC: 17

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	5	1	not provided (6)
-	1	1	Autosomal dominant nonsyndromic hearing loss 11 (2)
-	2	-	Autosomal recessive nonsyndromic hearing loss 2 (2)
-	2	-	Usher syndrome type 1 (2)
-	1	-	not specified (1)
-	1	-	Usher syndrome (1)
-	1	-	Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 (1)
-	1	-	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.037	T
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Benign	0.71	N
PhyloP100		0.56
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.25
Sift	Benign	0.051	T
Sift4G	Benign	0.18	T
Polyphen		0.30	B
Vest4		0.48
MVP		0.86
MPC		0.17
ClinPred		0.065	T
GERP RS		5.4
PromoterAI		0.017	Neutral
Varity_R		0.086
gMVP		0.45
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs140559111; hg19: chr11-76890940; COSMIC: COSV68684538; COSMIC: COSV68684538;