rs776570317

Variant names:

• chr19-50276094-G-T
• rs776570317
• NM_001145809.2:c.3571G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001145809.2(MYH14):​c.3571G>T​(p.Ala1191Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,457,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 1 publications found

Genes affected

MYH14 (HGNC:23212): (myosin heavy chain 14) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

MYH14 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 4A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14185762).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.3571G>T	p.Ala1191Ser	missense_variant	Exon 28 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.3472G>T	p.Ala1158Ser	missense_variant	Exon 27 of 42		NP_001070654.1
MYH14	NM_024729.4	c.3448G>T	p.Ala1150Ser	missense_variant	Exon 26 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.3571G>T	p.Ala1191Ser	missense_variant	Exon 28 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1457270 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 724562

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 85282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1110496

Other (OTH) AF: 0.00 AC: 0 AN: 60156

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Ala1191Ser va riant in MYH14 has not been previously reported in individuals with hearing loss , but has been identified in 1/44386 of European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs776570317). Alth ough this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Alanine (Ala) at position 1191 is not conserved in mammals or evolutionarily distant species and 9 species (Opossum, white-throated sparrow, medium ground finch, zebra finch, tibetan ground jay, tu rkey, X tropicalis, tetraodon and lamprey) carry a serine (Ser) at this position , raising the possibility that this change may be tolerated. Additional computat ional prediction tools suggest that the p.Ala1191Ser variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, while the clinical significance of the p.Ala1191Ser variant is unc ertain, its presence in various species suggests that it is more likely to be be nign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;.;T;.;.;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.82	.;T;T;.;T;.;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	.;.;L;.;.;L;.
PhyloP100		1.3
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.1	.;N;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.27	.;T;.;.;.;.;.
Sift4G	Benign	0.39	T;T;T;.;T;T;T
Polyphen		0.56	P;P;B;P;P;B;.
Vest4		0.17
MutPred		0.57		.;.;Gain of phosphorylation at A1150 (P = 0.0019);.;.;Gain of phosphorylation at A1150 (P = 0.0019);.;
MVP		0.81
MPC		0.21
ClinPred		0.23	T
GERP RS		3.5
Varity_R		0.066
gMVP		0.26
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs776570317; hg19: chr19-50779351;