chr11-77142763-G-A

Variant names:

• chr11-77142763-G-A
• rs782252317
• NM_000260.4:c.73G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_000260.4(MYO7A):​c.73G>A​(p.Gly25Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,459,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001396692: Experimental studies have shown that this missense change affects MYO7A function (PMID:18700726)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G25G) has been classified as Likely benign. The gene MYO7A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.60
• Publications: 13 publications found

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]

MYO7A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for MYO7A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001396692: Experimental studies have shown that this missense change affects MYO7A function (PMID: 18700726).; SCV004038877: The most pronounced variant effect results in completely abolishment of the actin-translocating activity and the actin activated-ATPase activity in-vitro. PMID: 34148116, 27460420, 25575603, 15660226, 18700726
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 11-77142763-G-A is Pathogenic according to our data. Variant chr11-77142763-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 177722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.73G>A	p.Gly25Arg	missense	Exon 3 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.73G>A	p.Gly25Arg	missense	Exon 3 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.40G>A	p.Gly14Arg	missense	Exon 4 of 50	NP_001356294.1	Q13402-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.73G>A	p.Gly25Arg	missense	Exon 3 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.73G>A	p.Gly25Arg	missense	Exon 3 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.40G>A	p.Gly14Arg	missense	Exon 4 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000817 AC: 2 AN: 244894 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459896 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 725952

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000225 AC: 1 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111320

Other (OTH) AF: 0.0000166 AC: 1 AN: 60314

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000946 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Rare genetic deafness (1)
1	-	-	Retinal dystrophy (1)
1	-	-	Usher syndrome (1)
1	-	-	Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 (1)
1	-	-	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.59		Loss of ubiquitination at K29 (P = 0.0505)
MVP		0.94
MPC		0.51
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs782252317; hg19: chr11-76853809; COSMIC: COSV105342021;