rs1554210769

Variant names:

• chr6-75857123-A-G
• rs1554210769
• NM_004999.4:c.1250A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004999.4(MYO6):​c.1250A>G​(p.Asn417Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.07

Genes affected

MYO6 (HGNC:7605): (myosin VI) This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2980265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.1250A>G	p.Asn417Ser	missense_variant	Exon 13 of 35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.1250A>G	p.Asn417Ser	missense_variant	Exon 13 of 35	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461728 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 27, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn417Ser variant in MYO6 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational pr ediction tools and conservation analyses suggest that the p.Asn417Ser variant ma y not impact the protein, though this information is not predictive enough to ru le out pathogenicity. In summary, the clinical significance of the p.Asn417Ser v ariant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.20
DEOGEN2	Benign	0.26	T;.;.;.;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.24	.;N;N;N;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.76	N;N;N;.;N;.
REVEL	Uncertain	0.39
Sift	Benign	0.98	T;T;T;.;T;.
Sift4G	Benign	0.87	T;T;T;T;T;T
Polyphen		0.033, 0.0020	.;B;B;B;.;.
Vest4		0.40
MutPred		0.53		Gain of disorder (P = 0.1033);Gain of disorder (P = 0.1033);Gain of disorder (P = 0.1033);Gain of disorder (P = 0.1033);Gain of disorder (P = 0.1033);Gain of disorder (P = 0.1033);
MVP		0.80
MPC		0.21
ClinPred		0.82	D
GERP RS		5.8
gMVP		0.36

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: rs1554210769; hg19: chr6-76566840;