rs782279338

Variant names:

• chr11-77160265-C-T
• rs782279338
• NM_000260.4:c.1183C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-77160265-C-T
• chr11-77160265-C-A
• chr11-77160265-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP1_Strong PM3 PP3

This summary comes from the ClinGen Evidence Repository: The c.1183C>T variant in MYO7A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 395. The highest population minor allele frequency in gnomAD v4.1 is 0.00008472 (2/23608 alleles) in the South Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.773, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 6 individuals with nonsyndromic genetic hearing loss. Out of 3 of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant for Usher syndrome and none of those were confirmed in trans (c.401T>A (p.Ile134Asn), 0 PM3 points, SCV: SCV001232108.5, Invitae). The other 2 were compound heterozygous for the variant and a variant of uncertain significance for nonsyndromic genetic hearing loss, 1 of them was confirmed in trans by family testing (0.25 PM3 points, c.1496T>C (p.Ile499Thr); c.1496T>C(p.Ile499Thr), PMIDs: 34416374, 34979615). 3 individuals were homozygous for the variant (1 PM3 point, PMIDs: 23770805, 27573290, ClinVar SCV: SCV001232108.5, Invitae) (PM3). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 8 affected family members from 3 families (PP1_Strong; PMIDs: 23770805, 27573290, 34979615). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_Strong, PM3, PP3. (ClinGen Hearing Loss VCEP specifications version 2; 7/23/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA6197402/MONDO:0019497/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 1.56
• Publications: 7 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

Specifications for MYO7A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.1183C>T	p.Arg395Cys	missense	Exon 11 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.1183C>T	p.Arg395Cys	missense	Exon 11 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.1150C>T	p.Arg384Cys	missense	Exon 12 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.1183C>T	p.Arg395Cys	missense	Exon 11 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.1183C>T	p.Arg395Cys	missense	Exon 11 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.1150C>T	p.Arg384Cys	missense	Exon 12 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000230 AC: 4 AN: 174104 AF XY: 0.0000214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000736

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 18 AN: 1416370 Hom.: 0 Cov.: 31 AF XY: 0.00000714 AC XY: 5 AN XY: 700400

African (AFR) AF: 0.00 AC: 0 AN: 32242

American (AMR) AF: 0.0000520 AC: 2 AN: 38472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25342

East Asian (EAS) AF: 0.00 AC: 0 AN: 36838

South Asian (SAS) AF: 0.0000499 AC: 4 AN: 80144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1089530

Other (OTH) AF: 0.0000170 AC: 1 AN: 58782

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000731 Hom.: 0

ExAC AF: 0.0000170 AC: 2

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Hearing loss, autosomal recessive (1)
1	-	-	Nonsyndromic genetic hearing loss (1)
1	-	-	not provided (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 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.89		Loss of disorder (P = 0.0372)
MVP		0.91
MPC		0.52
ClinPred		0.96	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.91
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs782279338; hg19: chr11-76871311; COSMIC: COSV68683740;