19-50301764-G-A

Position:

• chr19-50301764-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145809.2(MYH14):​c.5573G>A​(p.Arg1858His) variant causes a missense change. The variant allele was found at a frequency of 0.000296 in 1,613,918 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (3 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.75

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009919584).
• BP6: Variant 19-50301764-G-A is Benign according to our data. Variant chr19-50301764-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00132 (201/152300) while in subpopulation AFR AF= 0.00423 (176/41568). AF 95% confidence interval is 0.00372. There are 2 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 201 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.5573G>A	p.Arg1858His	missense_variant	40/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.5474G>A	p.Arg1825His	missense_variant	39/42		NP_001070654.1
MYH14	NM_024729.4	c.5450G>A	p.Arg1817His	missense_variant	38/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.5573G>A	p.Arg1858His	missense_variant	40/43		NM_001145809.2	ENSP00000493594

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152182 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

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: 0.000103

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000394 AC: 98 AN: 248486 Hom.: 1 AF XY: 0.000311 AC XY: 42 AN XY: 134922

Gnomad AFR exome AF: 0.00512

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000189 AC: 276 AN: 1461618 Hom.: 3 Cov.: 31 AF XY: 0.000180 AC XY: 131 AN XY: 727100

Gnomad4 AFR exome AF: 0.00523

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152300 Hom.: 2 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74480

Gnomad4 AFR AF: 0.00423

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.00147

ESP6500AA AF: 0.00632 AC: 26

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000513 AC: 62

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 26, 2015	p.Arg1858His in exon 40 of MYH14: This variant is not expected to have clinical significance because it has been identified in 0.5% (52/9586) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs11882073). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 03, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;.;.;D;.;.;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.77	.;T;T;T;.;T;.
MetaRNN	Benign	0.0099	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.069	D
MutationAssessor	Uncertain	2.6	.;.;.;M;.;.;M
MutationTaster	Benign	0.80	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.5	.;.;D;.;.;.;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	.;.;D;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;.;D;D
Polyphen		0.72	P;.;P;P;P;P;P
Vest4		0.091
MVP		0.65
MPC		0.19
ClinPred		0.034	T
GERP RS		3.1
Varity_R		0.075
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11882073; hg19: chr19-50805021;