rs782311929

Variant names:

• chr11-77172767-G-A
• rs782311929
• NM_000260.4:c.1817G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77172767-G-A
• chr11-77172767-G-C
• chr11-77172767-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM3 PP3

This summary comes from the ClinGen Evidence Repository: The c.1817 G>A (NM_000260.4(MYO7A):c.1817G>A (p.Arg606His)) variant in MYO7A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 606. The highest major allele frequency in gnomAD v2.1.1 is 0.00035 (0.035 % or 8/23092 alleles) in the South Asian population (PM2_supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.832, (which is above the threshold of 0.7), evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least one individual with autosomal recessive nonsyndromic genetic hearing loss. This proband was compound heterozygous for the variant and a pathogenic variant, confirmed in trans by parental testing (PM3; 1.0 point; LMM Internal Data). The patient with this variant displayed moderate to severe sensorineural hearing loss, although no vision anomalies or difficulty seeing at night were noted (PP4 not met; LMM Internal Data). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive nonsyndromic genetic deafness, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: (PP3, PM3; Version 2, 7.19.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA6197622/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:8
• Conservation: PhyloP100: 7.66
• Publications: 2 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 3 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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.1817G>A	p.Arg606His	missense	Exon 16 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.1817G>A	p.Arg606His	missense	Exon 16 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.1784G>A	p.Arg595His	missense	Exon 17 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.1817G>A	p.Arg606His	missense	Exon 16 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.1817G>A	p.Arg606His	missense	Exon 16 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.1784G>A	p.Arg595His	missense	Exon 17 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000845 AC: 14 AN: 165774 AF XY: 0.000113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000512 AC: 72 AN: 1406332 Hom.: 0 Cov.: 31 AF XY: 0.0000547 AC XY: 38 AN XY: 694422

African (AFR) AF: 0.0000314 AC: 1 AN: 31846

American (AMR) AF: 0.00 AC: 0 AN: 36918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25258

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36134

South Asian (SAS) AF: 0.000365 AC: 29 AN: 79498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5414

European-Non Finnish (NFE) AF: 0.0000369 AC: 40 AN: 1083892

Other (OTH) AF: 0.0000172 AC: 1 AN: 58286

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000889 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000531 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Autosomal dominant nonsyndromic hearing loss 11 (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	1	-	Nonsyndromic genetic hearing loss (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.94
MPC		0.52
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.57
gMVP		0.48
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782311929; hg19: chr11-76883813; COSMIC: COSV107515279; COSMIC: COSV107515279;