NM_000260.4:c.4323+35G>T

Variant names:

• chr11-77194559-G-T
• rs1109977
• NM_000260.4:c.4323+35G>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.4323+35G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,548,086 control chromosomes in the GnomAD database, including 231,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26133 hom., cov: 33)
  • Exomes 𝑓: 0.54 (205809 hom.)
• Consequence: MYO7A NM_000260.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.45
• 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=-0.91).
• BP6: Variant 11-77194559-G-T is Benign according to our data. Variant chr11-77194559-G-T is described in ClinVar as Benign. ClinVar VariationId is 255663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4323+35G>T		intron_variant	Intron 32 of 48	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4323+35G>T		intron_variant	Intron 32 of 48	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4323+35G>T		intron_variant	Intron 32 of 48	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4290+35G>T		intron_variant	Intron 33 of 49	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1866+35G>T		intron_variant	Intron 12 of 28	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2163+35G>T		intron_variant	Intron 15 of 31			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88169 AN: 151898 Hom.: 26081 Cov.: 33

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.576

GnomAD2 exomes AF: 0.549 AC: 89870 AN: 163652 AF XY: 0.534

Gnomad AFR exome AF: 0.681

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.483

Gnomad FIN exome AF: 0.630

Gnomad NFE exome AF: 0.549

Gnomad OTH exome AF: 0.522

GnomAD4 exome AF: 0.539 AC: 753101 AN: 1396068 Hom.: 205809 Cov.: 35 AF XY: 0.533 AC XY: 367176 AN XY: 688278

African (AFR) AF: 0.675 AC: 21409 AN: 31728

American (AMR) AF: 0.658 AC: 23732 AN: 36076

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 9736 AN: 24058

East Asian (EAS) AF: 0.473 AC: 17256 AN: 36456

South Asian (SAS) AF: 0.372 AC: 28817 AN: 77440

European-Finnish (FIN) AF: 0.623 AC: 30238 AN: 48554

Middle Eastern (MID) AF: 0.442 AC: 2405 AN: 5440

European-Non Finnish (NFE) AF: 0.546 AC: 589227 AN: 1078324

Other (OTH) AF: 0.522 AC: 30281 AN: 57992

GnomAD4 genome AF: 0.581 AC: 88289 AN: 152018 Hom.: 26133 Cov.: 33 AF XY: 0.581 AC XY: 43200 AN XY: 74304

African (AFR) AF: 0.678 AC: 28129 AN: 41488

American (AMR) AF: 0.624 AC: 9538 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1413 AN: 3468

East Asian (EAS) AF: 0.465 AC: 2400 AN: 5158

South Asian (SAS) AF: 0.348 AC: 1679 AN: 4822

European-Finnish (FIN) AF: 0.625 AC: 6610 AN: 10576

Middle Eastern (MID) AF: 0.479 AC: 139 AN: 290

European-Non Finnish (NFE) AF: 0.541 AC: 36716 AN: 67914

Other (OTH) AF: 0.573 AC: 1212 AN: 2114

Alfa AF: 0.545 Hom.: 22172

Bravo AF: 0.590

Asia WGS AF: 0.436 AC: 1519 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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1 Benign:1

Sep 05, 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	-0.91
CADD	Benign	0.021
DANN	Benign	0.65
PhyloP100		-1.4
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: rs1109977; hg19: chr11-76905604; COSMIC: COSV68686742; COSMIC: COSV68686742;