rs111033227

Positions:

• chr11-77162338-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000260.4(MYO7A):​c.1554+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,551,032 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (11 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, intron
• Scores: Splicing: ADA: 0.0008540
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -0.862

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-77162338-G-A is Benign according to our data. Variant chr11-77162338-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43150.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=2, Likely_benign=3}. Variant chr11-77162338-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00242 (368/152294) while in subpopulation NFE AF= 0.00362 (246/68036). AF 95% confidence interval is 0.00324. There are 2 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.1554+8G>A		splice_region_variant, intron_variant		ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.1554+8G>A		splice_region_variant, intron_variant		1	NM_000260.4
MYO7A	ENST00000409619.6	c.1521+8G>A		splice_region_variant, intron_variant		1
MYO7A	ENST00000458637.6	c.1554+8G>A		splice_region_variant, intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 368 AN: 152176 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00255 AC: 396 AN: 155382 Hom.: 2 AF XY: 0.00266 AC XY: 219 AN XY: 82210

Gnomad AFR exome AF: 0.000752

Gnomad AMR exome AF: 0.000567

Gnomad ASJ exome AF: 0.00200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000746

Gnomad FIN exome AF: 0.00595

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00390

GnomAD4 exome AF: 0.00330 AC: 4618 AN: 1398738 Hom.: 11 Cov.: 31 AF XY: 0.00330 AC XY: 2275 AN XY: 689892

Gnomad4 AFR exome AF: 0.000285

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.00163

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000543

Gnomad4 FIN exome AF: 0.00680

Gnomad4 NFE exome AF: 0.00370

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00242 AC: 368 AN: 152294 Hom.: 2 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74452

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00801

Gnomad4 NFE AF: 0.00362

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00293 Hom.: 0

Bravo AF: 0.00183

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2018	This variant is associated with the following publications: (PMID: 22135276, 16470552) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	MYO7A: BP4 -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 20, 2015

c.1554+8G>A in intron 13 of MYO7A: This variant is not expected to have clinical significance because it is not located within the conserved region of the splic e consensus sequence and has been identified in 1.7% (5/298) of Finnish chromoso mes and in 0.4% (33/8958) of European chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033227. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Usher syndrome type 1B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.3
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00085
dbscSNV1_RF	Benign	0.014
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

Publications

LitVar

Other links and lift over

dbSNP: rs111033227; hg19: chr11-76873384;