rs750358148

Positions:

• chr11-77190117-C-A
• chr11-77190117-C-G
• chr11-77190117-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000260.4(MYO7A):​c.3728C>A​(p.Pro1243Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1243L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.44

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 Pathogenic. Variant got 10 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77190117-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 11-77190117-C-A is Pathogenic according to our data. Variant chr11-77190117-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3601475.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.3728C>A	p.Pro1243Gln	missense_variant	29/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.3728C>A	p.Pro1243Gln	missense_variant	29/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.3728C>A	p.Pro1243Gln	missense_variant	29/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.3695C>A	p.Pro1232Gln	missense_variant	30/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1271C>A	p.Pro424Gln	missense_variant	9/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1568C>A		non_coding_transcript_exon_variant	12/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181858 Hom.: 0 AF XY: 0.0000205 AC XY: 2 AN XY: 97754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000153

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: 0.00000141 AC: 2 AN: 1419842 Hom.: 0 Cov.: 32 AF XY: 0.00000285 AC XY: 2 AN XY: 702398

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000534

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Institute of Rare Diseases, West China Hospital, Sichuan University

Jan 09, 2025

PM3_Strong;PM5;PM2_Supporting;PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.6	H;H;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.5	D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.85
MutPred		0.62		Loss of catalytic residue at P1243 (P = 0.021);Loss of catalytic residue at P1243 (P = 0.021);.;.;
MVP		0.94
MPC		0.43
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.90

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: rs750358148; hg19: chr11-76901162;