rs876657655

Variant names:

• chr11-77211162-A-G
• rs876657655
• NM_000260.4:c.6062A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PM3 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.6062A>G (NM_000260.4(MYO7A):c.6062A>G (p.Lys2021Arg)) variant in MYO7A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 2021. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.748, 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 4 individuals with Usher Syndrome type 1 (from three families). For one of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant (phase unknown) ((NM_000260.4(MYO7A):c.722G>A (p.Arg241His); 0.5 PM3 points; 21436283). In another family, this variant was found in the homozygous state in a male adolescent, 14 years of age, with bilateral congenital hearing loss and features of night blindness (0.5 PM3 points; Allan, 2014; 1). Due to consanguinity, 2 individuals from the same family were homozygous for the variant (0.25 PM3 points; Allam, 2014; 1) (PM3). At least one patient with this disease displayed sensorineural hearing loss and retinitis pigmentosa, which is highly specific for Usher Syndrome 1 (PMID:21436283; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_supporting, PP3, PM3, PP4; Version 2; 2022).1. https://docs.google.com/document/d/17VJ_cidV8dqRQMHTzSVrFa-7PrmJ4trkw2wQsNEPqvk/edit LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576905/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:2
• Conservation: PhyloP100: 7.06
• 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: Likely_pathogenic. The variant received 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.6062A>G	p.Lys2021Arg	missense	Exon 45 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.5948A>G	p.Lys1983Arg	missense	Exon 45 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.5915A>G	p.Lys1972Arg	missense	Exon 46 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.6062A>G	p.Lys2021Arg	missense	Exon 45 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.5948A>G	p.Lys1983Arg	missense	Exon 45 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.5915A>G	p.Lys1972Arg	missense	Exon 46 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426868 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 705974

African (AFR) AF: 0.00 AC: 0 AN: 32726

American (AMR) AF: 0.00 AC: 0 AN: 40050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25400

East Asian (EAS) AF: 0.00 AC: 0 AN: 37910

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1093974

Other (OTH) AF: 0.00 AC: 0 AN: 59066

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Usher syndrome type 1 (3)
-	1	-	not provided (1)
1	-	-	Rare genetic deafness (1)
-	1	-	Usher syndrome type 1;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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.75
Sift	Benign	0.044	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.50		Loss of methylation at K2021 (P = 0.0092)
MVP		0.89
MPC		0.42
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.84
gMVP		0.65
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs876657655; hg19: chr11-76922207;