rs397516327

Variant names:

• chr11-77211265-C-A
• rs397516327
• NM_000260.4:c.6165C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77211265-C-A
• chr11-77211265-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000260.4(MYO7A):​c.6165C>A​(p.Ser2055Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2055S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680
• Publications: 2 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33405364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6165C>A	p.Ser2055Arg	missense_variant	Exon 45 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6165C>A	p.Ser2055Arg	missense_variant	Exon 45 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.6051C>A	p.Ser2017Arg	missense_variant	Exon 45 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.6018C>A	p.Ser2006Arg	missense_variant	Exon 46 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3591C>A	p.Ser1197Arg	missense_variant	Exon 25 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*737C>A		non_coding_transcript_exon_variant	Exon 28 of 32			ENSP00000499323.1
MYO7A	ENST00000670577.1	n.*737C>A		3_prime_UTR_variant	Exon 28 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428586 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707412

African (AFR) AF: 0.00 AC: 0 AN: 32802

American (AMR) AF: 0.00 AC: 0 AN: 39748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25484

East Asian (EAS) AF: 0.00 AC: 0 AN: 37834

South Asian (SAS) AF: 0.00 AC: 0 AN: 81098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51154

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095510

Other (OTH) AF: 0.00 AC: 0 AN: 59220

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	L;.;.;.
PhyloP100		-0.068
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.29
Sift	Benign	0.23	T;T;T;D
Sift4G	Benign	0.33	T;T;T;D
Polyphen		0.46	P;.;.;.
Vest4		0.61
MutPred		0.38		Loss of ubiquitination at K2058 (P = 0.0428);.;.;.;
MVP		0.82
MPC		0.12
ClinPred		0.98	D
GERP RS		-2.3
Varity_R		0.80
gMVP		0.40
Mutation Taster		=44/56	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: rs397516327; hg19: chr11-76922310;