rs201251963

Positions:

• chr11-77199723-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000260.4(MYO7A):​c.4757A>G​(p.Asn1586Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,613,638 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 8.58

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009866029).
• BP6: Variant 11-77199723-A-G is Benign according to our data. Variant chr11-77199723-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196935.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4757A>G	p.Asn1586Ser	missense_variant	35/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4757A>G	p.Asn1586Ser	missense_variant	35/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4643A>G	p.Asn1548Ser	missense_variant	35/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4610A>G	p.Asn1537Ser	missense_variant	36/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2186A>G	p.Asn729Ser	missense_variant	15/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2597A>G		non_coding_transcript_exon_variant	18/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000423 AC: 105 AN: 248384 Hom.: 1 AF XY: 0.000363 AC XY: 49 AN XY: 134820

Gnomad AFR exome AF: 0.000520

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00473

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000135 AC: 197 AN: 1461324 Hom.: 2 Cov.: 33 AF XY: 0.000129 AC XY: 94 AN XY: 726932

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00267

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74462

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000350 Hom.: 1

Bravo AF: 0.000336

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00123 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000364 AC: 44

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.4757A>G (p.N1586S) alteration is located in exon 35 (coding exon 34) of the MYO7A gene. This alteration results from a A to G substitution at nucleotide position 4757, causing the asparagine (N) at amino acid position 1586 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 26, 2017

p.Asn1586Ser variant in exon 35 of MYO7A: This variant is not expected to have c linical significance because it has been identified in 0.5% of East Asian chrom osomes including 1 homozygote by the genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs201251963). -

Usher syndrome type 1B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

May 20, 2020

- -

MYO7A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0099	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.5	L;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.38	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.35	B;.;.;.
Vest4		0.80
MVP		0.83
MPC		0.42
ClinPred		0.095	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201251963; hg19: chr11-76910768;