rs2276289

Variant names:

• chr11-77213085-A-T
• rs2276289
• NM_000260.4:c.6438+50A>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.6438+50A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.94 in 1,435,954 control chromosomes in the GnomAD database, including 639,293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (59128 hom., cov: 30)
  • Exomes 𝑓: 0.95 (580165 hom.)
• Consequence: MYO7A NM_000260.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.908
• Publications: 9 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=-0.95).
• BP6: Variant 11-77213085-A-T is Benign according to our data. Variant chr11-77213085-A-T is described in ClinVar as Benign. ClinVar VariationId is 255665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6438+50A>T		intron_variant	Intron 47 of 48	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6438+50A>T		intron_variant	Intron 47 of 48	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.6318+50A>T		intron_variant	Intron 47 of 48	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.6291+50A>T		intron_variant	Intron 48 of 49	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3864+50A>T		intron_variant	Intron 27 of 28	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*1010+50A>T		intron_variant	Intron 30 of 31			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132500 AN: 152020 Hom.: 59082 Cov.: 30

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.981

Gnomad AMR AF: 0.896

Gnomad ASJ AF: 0.976

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.895

Gnomad FIN AF: 0.960

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.885

GnomAD2 exomes AF: 0.914 AC: 143017 AN: 156556 AF XY: 0.918

Gnomad AFR exome AF: 0.657

Gnomad AMR exome AF: 0.881

Gnomad ASJ exome AF: 0.976

Gnomad EAS exome AF: 0.774

Gnomad FIN exome AF: 0.958

Gnomad NFE exome AF: 0.970

Gnomad OTH exome AF: 0.932

GnomAD4 exome AF: 0.949 AC: 1217908 AN: 1283816 Hom.: 580165 Cov.: 18 AF XY: 0.948 AC XY: 606290 AN XY: 639468

African (AFR) AF: 0.673 AC: 19468 AN: 28922

American (AMR) AF: 0.881 AC: 31250 AN: 35484

Ashkenazi Jewish (ASJ) AF: 0.977 AC: 23880 AN: 24438

East Asian (EAS) AF: 0.759 AC: 26731 AN: 35220

South Asian (SAS) AF: 0.896 AC: 68681 AN: 76674

European-Finnish (FIN) AF: 0.962 AC: 47409 AN: 49284

Middle Eastern (MID) AF: 0.949 AC: 4775 AN: 5030

European-Non Finnish (NFE) AF: 0.970 AC: 945460 AN: 974608

Other (OTH) AF: 0.928 AC: 50254 AN: 54156

GnomAD4 genome AF: 0.872 AC: 132602 AN: 152138 Hom.: 59128 Cov.: 30 AF XY: 0.871 AC XY: 64770 AN XY: 74390

African (AFR) AF: 0.676 AC: 28023 AN: 41434

American (AMR) AF: 0.896 AC: 13706 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.976 AC: 3387 AN: 3472

East Asian (EAS) AF: 0.759 AC: 3928 AN: 5172

South Asian (SAS) AF: 0.895 AC: 4306 AN: 4810

European-Finnish (FIN) AF: 0.960 AC: 10194 AN: 10618

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.971 AC: 66014 AN: 68016

Other (OTH) AF: 0.884 AC: 1870 AN: 2116

Alfa AF: 0.928 Hom.: 12134

Bravo AF: 0.858

Asia WGS AF: 0.832 AC: 2894 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.95
CADD	Benign	0.48
DANN	Benign	0.46
PhyloP100		-0.91
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: rs2276289; hg19: chr11-76924130;