NM_000260.4:c.5101C>G

Variant names:

• chr11-77202357-C-G
• rs111033182
• NM_000260.4:c.5101C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000260.4(MYO7A):​c.5101C>G​(p.Arg1701Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. R1701Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.510
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11633369).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5101C>G	p.Arg1701Gly	missense_variant	Exon 37 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5101C>G	p.Arg1701Gly	missense_variant	Exon 37 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4987C>G	p.Arg1663Gly	missense_variant	Exon 37 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4954C>G	p.Arg1652Gly	missense_variant	Exon 38 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2527C>G	p.Arg843Gly	missense_variant	Exon 17 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2941C>G		non_coding_transcript_exon_variant	Exon 20 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418348 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 701466

African (AFR) AF: 0.00 AC: 0 AN: 32496

American (AMR) AF: 0.00 AC: 0 AN: 38550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25428

East Asian (EAS) AF: 0.00 AC: 0 AN: 37396

South Asian (SAS) AF: 0.00 AC: 0 AN: 80504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089156

Other (OTH) AF: 0.00 AC: 0 AN: 58780

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.
PhyloP100		0.51
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.092
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.45
MutPred		0.38		Loss of solvent accessibility (P = 0.0017);.;.;.;
MVP		0.74
MPC		0.11
ClinPred		0.15	T
GERP RS		2.9
Varity_R		0.13
gMVP		0.27
Mutation Taster		=85/15	polymorphism

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: rs111033182; hg19: chr11-76913402;