rs113993956

chr19-50268255-G-Achr19-50268255-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145809.2(MYH14):c.2921G>A(p.Arg974His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,571,088 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R974L) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.04

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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-50268255-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 30739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.015891105).
• BP6: Variant 19-50268255-G-A is Benign according to our data. Variant chr19-50268255-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 721130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000788 (12/152338) while in subpopulation AMR AF= 0.000588 (9/15308). AF 95% confidence interval is 0.000306. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.2921G>A	p.Arg974His	missense_variant	24/43	ENST00000642316.2
MYH14	NM_001077186.2	c.2822G>A	p.Arg941His	missense_variant	23/42
MYH14	NM_024729.4	c.2798G>A	p.Arg933His	missense_variant	22/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.2921G>A	p.Arg974His	missense_variant	24/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000623 AC: 115 AN: 184528 Hom.: 0 AF XY: 0.000465 AC XY: 46 AN XY: 98942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000230

Gnomad SAS exome AF: 0.000207

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000252

Gnomad OTH exome AF: 0.000616

GnomAD4 exome AF: 0.000113 AC: 160 AN: 1418750 Hom.: 0 Cov.: 32 AF XY: 0.000103 AC XY: 72 AN XY: 701990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000539

Gnomad4 SAS exome AF: 0.000137

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000128

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000844 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.000251 AC: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2021	This variant is associated with the following publications: (PMID: 26969326) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	- -

MYH14-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.41	N
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.016	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
Sift4G	Uncertain	0.029	D;D;D;.;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D
Vest4		0.20
MVP		0.85
MPC		1.5
ClinPred		0.12	T
GERP RS		3.9
Varity_R		0.049
gMVP		0.33

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: rs113993956; hg19: chr19-50771512; COSMIC: COSV51834076; COSMIC: COSV51834076;