rs948962

Variant names:

• chr11-77208433-C-A
• rs948962
• NM_000260.4:c.5860C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77208433-C-A
• chr11-77208433-C-G
• chr11-77208433-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.5860C>A​(p.Leu1954Ile) variant causes a missense change. The variant allele was found at a frequency of 0.472 in 1,602,936 control chromosomes in the GnomAD database, including 184,200 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1954V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.53 (22476 hom., cov: 33)
  • Exomes 𝑓: 0.47 (161724 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 5.96
• Publications: 41 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.922537E-6).
• BP6: Variant 11-77208433-C-A is Benign according to our data. Variant chr11-77208433-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

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.5860C>A	p.Leu1954Ile	missense	Exon 43 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.5746C>A	p.Leu1916Ile	missense	Exon 43 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.5713C>A	p.Leu1905Ile	missense	Exon 44 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.5860C>A	p.Leu1954Ile	missense	Exon 43 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.5746C>A	p.Leu1916Ile	missense	Exon 43 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.5713C>A	p.Leu1905Ile	missense	Exon 44 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80721 AN: 151740 Hom.: 22422 Cov.: 33

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.542

GnomAD2 exomes AF: 0.474 AC: 116423 AN: 245742 AF XY: 0.461

Gnomad AFR exome AF: 0.697

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.447

Gnomad EAS exome AF: 0.355

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.468

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.466 AC: 676045 AN: 1451080 Hom.: 161724 Cov.: 34 AF XY: 0.461 AC XY: 332593 AN XY: 721950

African (AFR) AF: 0.704 AC: 23416 AN: 33258

American (AMR) AF: 0.551 AC: 24414 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 11553 AN: 26048

East Asian (EAS) AF: 0.324 AC: 12829 AN: 39586

South Asian (SAS) AF: 0.317 AC: 27211 AN: 85788

European-Finnish (FIN) AF: 0.561 AC: 29854 AN: 53204

Middle Eastern (MID) AF: 0.539 AC: 3092 AN: 5738

European-Non Finnish (NFE) AF: 0.467 AC: 515596 AN: 1103088

Other (OTH) AF: 0.468 AC: 28080 AN: 60028

GnomAD4 genome AF: 0.532 AC: 80841 AN: 151856 Hom.: 22476 Cov.: 33 AF XY: 0.532 AC XY: 39442 AN XY: 74208

African (AFR) AF: 0.696 AC: 28870 AN: 41454

American (AMR) AF: 0.513 AC: 7835 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3470

East Asian (EAS) AF: 0.336 AC: 1731 AN: 5148

South Asian (SAS) AF: 0.311 AC: 1498 AN: 4818

European-Finnish (FIN) AF: 0.569 AC: 5995 AN: 10528

Middle Eastern (MID) AF: 0.534 AC: 155 AN: 290

European-Non Finnish (NFE) AF: 0.468 AC: 31786 AN: 67864

Other (OTH) AF: 0.540 AC: 1134 AN: 2100

Alfa AF: 0.484 Hom.: 79313

Bravo AF: 0.539

TwinsUK AF: 0.478 AC: 1774

ALSPAC AF: 0.461 AC: 1777

ESP6500AA AF: 0.689 AC: 2851

ESP6500EA AF: 0.481 AC: 4046

ExAC AF: 0.468 AC: 56555

Asia WGS AF: 0.362 AC: 1260 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Autosomal recessive nonsyndromic hearing loss 2 (3)
-	-	3	not provided (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 11 (2)
-	-	2	Usher syndrome type 1 (2)
-	-	1	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0000089	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.9	N
PhyloP100		6.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	1.9	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.15
MPC		0.091
ClinPred		0.0016	T
GERP RS		4.3
Varity_R		0.097
gMVP		0.13
Mutation Taster		=91/9	polymorphism (auto)

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: rs948962; hg19: chr11-76919478; COSMIC: COSV68684428; COSMIC: COSV68684428;