11-77189442-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 7P and 8B. PM1 PM2 PM5 PP3 BP4_Strong BS1

The NM_000260.4(MYO7A):c.3602G>C(p.Cys1201Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,613,886 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. C1201Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (1 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 7.75

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77189442-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374511.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.06198716).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00019 (29/152276) while in subpopulation EAS AF= 0.00542 (28/5168). AF 95% confidence interval is 0.00385. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.3602G>C	p.Cys1201Ser	missense_variant	28/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.3602G>C	p.Cys1201Ser	missense_variant	28/49	1	NM_000260.4

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00541

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000341 AC: 85 AN: 249124 Hom.: 1 AF XY: 0.000296 AC XY: 40 AN XY: 135188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00473

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461610 Hom.: 1 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00295

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74434

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00542

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000268

ExAC AF: 0.000298 AC: 36

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2021	Observed as heterozygous in multiple unrelated patients with hearing loss in published literature; patients either harbored no second MYO7A variant or few patient details were provided (Yoshimura et al., 2013; Nishio et al., 2015; Chen et al., 2016; Sun et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29625443, 27535533, 33111992, 25788563, 27610647, 24831256, 23237960, 30245029) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Autosomal dominant nonsyndromic hearing loss 11 Benign:2

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	-	- -

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Feb 08, 2017

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 13, 2016

p.Cys1201Ser in exon 28 of MYO7A: This variant is not expected to have clinical significance because it has been identified in 0.4% (36/8622) of East Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs117966637). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.1	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-9.1	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Benign	0.069	T;T;T;T
Polyphen		1.0	D;.;.;.
Vest4		0.93
MutPred		0.70		Gain of disorder (P = 0.1358);Gain of disorder (P = 0.1358);.;.;
MVP		0.98
MPC		0.51
ClinPred		0.19	T
GERP RS		5.4
Varity_R		0.87
gMVP		0.77

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: rs117966637; hg19: chr11-76900487;