rs373080197

Variant names:

• chr11-77194396-G-A
• rs373080197
• NM_000260.4:c.4195G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77194396-G-A
• chr11-77194396-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000260.4(MYO7A):​c.4195G>A​(p.Asp1399Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1399H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.56
• Publications: 0 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, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4195G>A	p.Asp1399Asn	missense_variant	Exon 32 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4195G>A	p.Asp1399Asn	missense_variant	Exon 32 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4195G>A	p.Asp1399Asn	missense_variant	Exon 32 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4162G>A	p.Asp1388Asn	missense_variant	Exon 33 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1738G>A	p.Asp580Asn	missense_variant	Exon 12 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2035G>A		non_coding_transcript_exon_variant	Exon 15 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.3	M;M;.;.
PhyloP100		9.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Benign	0.17	T;T;T;D
Polyphen		1.0	D;.;.;.
Vest4		0.90
MutPred		0.53		Loss of phosphorylation at Y1400 (P = 0.1093);Loss of phosphorylation at Y1400 (P = 0.1093);.;.;
MVP		0.92
MPC		0.46
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.49
gMVP		0.70
Mutation Taster		=45/55	disease causing

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: rs373080197; hg19: chr11-76905441;