rs41298757

Variant names:

• chr11-77211823-C-T
• rs41298757
• NM_000260.4:c.6240C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000260.4(MYO7A):​c.6240C>T​(p.Ser2080Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,613,416 control chromosomes in the GnomAD database, including 1,124 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (64 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1060 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.610

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 11-77211823-C-T is Benign according to our data. Variant chr11-77211823-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77211823-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.025 (3807/152284) while in subpopulation NFE AF= 0.0411 (2798/68010). AF 95% confidence interval is 0.0399. There are 64 homozygotes in gnomad4. There are 1796 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6240C>T	p.Ser2080Ser	splice_region_variant, synonymous_variant	Exon 46 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6240C>T	p.Ser2080Ser	splice_region_variant, synonymous_variant	Exon 46 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.6126C>T	p.Ser2042Ser	splice_region_variant, synonymous_variant	Exon 46 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.6093C>T	p.Ser2031Ser	splice_region_variant, synonymous_variant	Exon 47 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3666C>T	p.Ser1222Ser	splice_region_variant, synonymous_variant	Exon 26 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*812C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 29 of 32			ENSP00000499323.1
MYO7A	ENST00000670577	n.*812C>T		3_prime_UTR_variant	Exon 29 of 30			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3803 AN: 152166 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00746

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0258 AC: 6438 AN: 249220 Hom.: 136 AF XY: 0.0275 AC XY: 3719 AN XY: 135150

Gnomad AFR exome AF: 0.00698

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0219

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.0404

Gnomad OTH exome AF: 0.0275

GnomAD4 exome AF: 0.0345 AC: 50467 AN: 1461132 Hom.: 1060 Cov.: 31 AF XY: 0.0345 AC XY: 25087 AN XY: 726882

Gnomad4 AFR exome AF: 0.00654

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0212

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0400

Gnomad4 OTH exome AF: 0.0302

GnomAD4 genome AF: 0.0250 AC: 3807 AN: 152284 Hom.: 64 Cov.: 32 AF XY: 0.0241 AC XY: 1796 AN XY: 74454

Gnomad4 AFR AF: 0.00746

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0411

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0333 Hom.: 75

Bravo AF: 0.0242

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0454

EpiControl AF: 0.0462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 25, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2013

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. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Usher syndrome type 1B Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.2
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41298757; hg19: chr11-76922868;