rs189243324

Variant names:

• chr19-50252752-C-A
• rs189243324
• NM_001145809.2:c.1944C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50252752-C-A
• chr19-50252752-C-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.1944C>A​(p.Asp648Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000632 in 1,424,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D648D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense, splice_region
• Scores: Splicing: ADA: 0.00004499
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.78
• Publications: 0 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=0.25790125).
• 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.1944C>A	p.Asp648Glu	missense_variant, splice_region_variant	Exon 16 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.1944C>A	p.Asp648Glu	missense_variant, splice_region_variant	Exon 16 of 42		NP_001070654.1
MYH14	NM_024729.4	c.1920C>A	p.Asp640Glu	missense_variant, splice_region_variant	Exon 15 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.1944C>A	p.Asp648Glu	missense_variant, splice_region_variant	Exon 16 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000632 AC: 9 AN: 1424290 Hom.: 0 Cov.: 29 AF XY: 0.00000709 AC XY: 5 AN XY: 705494

African (AFR) AF: 0.00 AC: 0 AN: 32424

American (AMR) AF: 0.00 AC: 0 AN: 39320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25478

East Asian (EAS) AF: 0.00 AC: 0 AN: 37576

South Asian (SAS) AF: 0.00 AC: 0 AN: 81242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000824 AC: 9 AN: 1092692

Other (OTH) AF: 0.00 AC: 0 AN: 59060

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 15, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	0.0077	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.61	.;.;D;.;D;.;D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.93	.;D;D;.;D;T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.3	.;.;L;.;.;.;L
PhyloP100		-1.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	.;D;D;.;.;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.018	.;D;D;.;.;.;.
Sift4G	Benign	0.076	T;T;T;.;T;T;T
Polyphen		0.088	B;B;B;P;.;P;B
Vest4		0.56
MutPred		0.39		.;.;Gain of ubiquitination at K639 (P = 0.0817);.;.;.;Gain of ubiquitination at K639 (P = 0.0817);
MVP		0.91
MPC		1.3
ClinPred		0.51	D
GERP RS		-4.1
Varity_R		0.28
gMVP		0.43
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.20
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: rs189243324; hg19: chr19-50756009;