rs2276290

Variant names:

• chr11-77207452-G-A
• rs2276290
• NM_000260.4:c.5856+50G>A

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.5856+50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,327,794 control chromosomes in the GnomAD database, including 208,644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24124 hom., cov: 32)
  • Exomes 𝑓: 0.56 (184520 hom.)
• Consequence: MYO7A NM_000260.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.743
• Publications: 11 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, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.89).
• BP6: Variant 11-77207452-G-A is Benign according to our data. Variant chr11-77207452-G-A is described in ClinVar as [Benign]. Clinvar id is 255664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5856+50G>A		intron_variant	Intron 42 of 48	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5856+50G>A		intron_variant	Intron 42 of 48	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.5742+50G>A		intron_variant	Intron 42 of 48	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.5709+50G>A		intron_variant	Intron 43 of 49	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3282+50G>A		intron_variant	Intron 22 of 28	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*454+50G>A		intron_variant	Intron 25 of 31			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85176 AN: 151872 Hom.: 24084 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.576

GnomAD2 exomes AF: 0.561 AC: 95601 AN: 170476 AF XY: 0.550

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.670

Gnomad ASJ exome AF: 0.524

Gnomad EAS exome AF: 0.507

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.567

Gnomad OTH exome AF: 0.557

GnomAD4 exome AF: 0.558 AC: 655674 AN: 1175804 Hom.: 184520 Cov.: 16 AF XY: 0.552 AC XY: 326654 AN XY: 591464

African (AFR) AF: 0.539 AC: 14620 AN: 27134

American (AMR) AF: 0.664 AC: 24086 AN: 36258

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 12412 AN: 23828

East Asian (EAS) AF: 0.480 AC: 16951 AN: 35304

South Asian (SAS) AF: 0.413 AC: 30983 AN: 74936

European-Finnish (FIN) AF: 0.649 AC: 32320 AN: 49804

Middle Eastern (MID) AF: 0.575 AC: 3028 AN: 5266

European-Non Finnish (NFE) AF: 0.565 AC: 493346 AN: 872440

Other (OTH) AF: 0.549 AC: 27928 AN: 50834

GnomAD4 genome AF: 0.561 AC: 85277 AN: 151990 Hom.: 24124 Cov.: 32 AF XY: 0.563 AC XY: 41799 AN XY: 74296

African (AFR) AF: 0.541 AC: 22412 AN: 41452

American (AMR) AF: 0.621 AC: 9489 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1834 AN: 3472

East Asian (EAS) AF: 0.484 AC: 2477 AN: 5120

South Asian (SAS) AF: 0.395 AC: 1902 AN: 4810

European-Finnish (FIN) AF: 0.649 AC: 6873 AN: 10582

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.564 AC: 38352 AN: 67964

Other (OTH) AF: 0.575 AC: 1212 AN: 2108

Alfa AF: 0.564 Hom.: 4470

Bravo AF: 0.562

Asia WGS AF: 0.437 AC: 1521 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.9
DANN	Benign	0.41
PhyloP100		-0.74
Mutation Taster		=100/0	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: rs2276290; hg19: chr11-76918497; COSMIC: COSV68683308; COSMIC: COSV68683308;