rs876657909

Positions:

• chr6-75886094-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_004999.4(MYO6):​c.2507G>A​(p.Arg836His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,446,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYO6 NM_004999.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.51

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]

MYO6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4	c.2507G>A	p.Arg836His	missense_variant, splice_region_variant	24/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.2507G>A	p.Arg836His	missense_variant, splice_region_variant	24/35	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1446058 Hom.: 0 Cov.: 27 AF XY: 0.00000278 AC XY: 2 AN XY: 720416

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: 0.00000546

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 30, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The c.2507G>A ( p.Arg836His) variant in MYO6 has not been previously reported in individuals wit h hearing loss and was absent from large population studies. This variant is loc ated at the last base of exon 24, which is a conserved nucleotide within the 5' splice site consensus region. Computational tools suggest a possible impact to s plicing; however, this information is not predictive enough to determine pathoge nicity. Additional computational prediction tools and conservation analyses do n ot provide strong support for or against an impact to the protein. In summary, w hile there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;.;.;.;T;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.1	.;M;M;M;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D;D;D;.;D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D;D;.;D;.
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.99, 1.0	.;D;D;D;.;.
Vest4		0.55
MutPred		0.63		Loss of methylation at R836 (P = 0.0491);Loss of methylation at R836 (P = 0.0491);Loss of methylation at R836 (P = 0.0491);Loss of methylation at R836 (P = 0.0491);Loss of methylation at R836 (P = 0.0491);Loss of methylation at R836 (P = 0.0491);
MVP		0.95
MPC		0.32
ClinPred		0.99	D
GERP RS		5.8
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.68		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876657909; hg19: chr6-76595811; COSMIC: COSV64117778; COSMIC: COSV64117778;