NM_000260.4:c.3560G>T

Variant names:

• chr11-77189400-G-T
• rs1555090314
• NM_000260.4:c.3560G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000260.4(MYO7A):​c.3560G>T​(p.Ser1187Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.52

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain MyTH4 1 (size 236) in uniprot entity MYO7A_HUMAN there are 26 pathogenic changes around while only 4 benign (87%) in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.3560G>T	p.Ser1187Ile	missense_variant	Exon 28 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.3560G>T	p.Ser1187Ile	missense_variant	Exon 28 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.3560G>T	p.Ser1187Ile	missense_variant	Exon 28 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.3527G>T	p.Ser1176Ile	missense_variant	Exon 29 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1103G>T	p.Ser368Ile	missense_variant	Exon 8 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1400G>T		non_coding_transcript_exon_variant	Exon 11 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYO7A c.3560G>T (p.Ser1187Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249114 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3560G>T has been reported in the literature in an individual affected with hearing loss who was compound heterozygous with a pathogenic variant (Kim_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26633542, 35853923). ClinVar contains an entry for this variant (Variation ID: 557219). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal dominant nonsyndromic hearing loss 11 Uncertain:1

Dec 21, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Mar 19, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.4	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.96
MutPred		0.80		Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);.;.;
MVP		0.99
MPC		0.51
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.84

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: rs1555090314; hg19: chr11-76900445;