rs121965081

chr11-77157000-G-Achr11-77157000-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000260.4(MYO7A):c.731G>A(p.Arg244His) variant causes a missense change. The variant allele was found at a frequency of 0.000431 in 1,612,286 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R244C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 6.67

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77156999-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2637024.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.731G>A	p.Arg244His	missense_variant	7/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.731G>A	p.Arg244His	missense_variant	7/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.731G>A	p.Arg244His	missense_variant	7/49	1		P1
MYO7A	ENST00000409619.6	c.698G>A	p.Arg233His	missense_variant	8/50	1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000270 AC: 67 AN: 247714 Hom.: 0 AF XY: 0.000208 AC XY: 28 AN XY: 134534

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000958

Gnomad NFE exome AF: 0.000498

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000447 AC: 653 AN: 1460094 Hom.: 1 Cov.: 32 AF XY: 0.000439 AC XY: 319 AN XY: 726276

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000761

Gnomad4 NFE exome AF: 0.000564

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74360

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000961 AC: 8

ExAC AF: 0.000339 AC: 41

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	MYO7A: PP3 -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 12, 2016

The p.Arg244His variant in MYO7A has been previously reported in one individual with hearing loss by our laboratory who had an alternate explanation for their h earing loss in another gene. In addition, it has been identified in 34/65670 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs121965081); however this frequency is not high enough to rule out a pathogenic role. A different amino acid change at the same position, p.Arg244Pro, has been reported in the homozygous state in 1 Chinese individual with hearing loss and vestibular dysfunction and segregated with disease in 2 af fected siblings (Liu 1997). Computational prediction tools and conservation anal ysis suggest the variant may impact the protein. These data suggest that variant s at this amino acid position are not tolerated; however this information is ins ufficient to assume pathogenicity. In summary, the clinical significance of the p.Arg244His is uncertain. -

Usher syndrome type 1B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D;T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	-0.55	N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.8	D;.;D;D
REVEL	Uncertain	0.63
Sift	Benign	0.41	T;.;T;T
Sift4G	Benign	0.65	T;T;T;T
Polyphen		0.97	D;.;.;.
Vest4		0.87
MVP		0.89
MPC		0.48
ClinPred		0.79	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs121965081; hg19: chr11-76868046;