chr11-77205485-A-G

Position:

• chr11-77205485-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000260.4(MYO7A):​c.5504A>G​(p.Glu1835Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.91

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 6 ACMG points.

• PM1: In a domain MyTH4 2 (size 149) in uniprot entity MYO7A_HUMAN there are 15 pathogenic changes around while only 5 benign (75%) in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5504A>G	p.Glu1835Gly	missense_variant	40/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5504A>G	p.Glu1835Gly	missense_variant	40/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.5390A>G	p.Glu1797Gly	missense_variant	40/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.5357A>G	p.Glu1786Gly	missense_variant	41/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2930A>G	p.Glu977Gly	missense_variant	20/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*102A>G		non_coding_transcript_exon_variant	23/32			ENSP00000499323.1
MYO7A	ENST00000670577.1	n.*102A>G		3_prime_UTR_variant	23/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432604 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 709868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 09, 2014

The Glu1835Gly variant in MYO7A has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein. In summary, the clinical significance of the Glu1835Gly varian t is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.1	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.89	P;.;.;.
Vest4		0.90
MutPred		0.69		Gain of catalytic residue at G1833 (P = 0.1191);.;.;.;
MVP		0.99
MPC		0.25
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs727503331; hg19: chr11-76916530;