rs192745436

Positions:

• chr19-50255266-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001145809.2(MYH14):​c.1992G>A​(p.Pro664=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00074 in 1,551,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.248

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-50255266-G-A is Benign according to our data. Variant chr19-50255266-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50255266-G-A is described in Lovd as [Benign]. Variant chr19-50255266-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.248 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000868 (132/152102) while in subpopulation AFR AF= 0.00157 (65/41474). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.1992G>A	p.Pro664=	synonymous_variant	17/43	ENST00000642316.2
MYH14	NM_001077186.2	c.1946-2033G>A		intron_variant
MYH14	NM_024729.4	c.1922-2033G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.1992G>A	p.Pro664=	synonymous_variant	17/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.000869 AC: 132 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000727 AC: 112 AN: 153978 Hom.: 0 AF XY: 0.000612 AC XY: 50 AN XY: 81706

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.000648

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00253

GnomAD4 exome AF: 0.000726 AC: 1016 AN: 1399172 Hom.: 0 Cov.: 31 AF XY: 0.000716 AC XY: 494 AN XY: 690112

Gnomad4 AFR exome AF: 0.00193

Gnomad4 AMR exome AF: 0.000980

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.000810

Gnomad4 OTH exome AF: 0.000672

GnomAD4 genome AF: 0.000868 AC: 132 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000726 AC XY: 54 AN XY: 74332

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000777 Hom.: 0

Bravo AF: 0.000914

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 25, 2013	Pro664Pro in Exon 17 of MYH14: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.02% (4/2178) chrom osomes by the 1000 Genomes Project (dbSNP rs192745436). -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MYH14: BP4, BP7, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.5
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs192745436; hg19: chr19-50758523;