rs727503228

chr19-50289626-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.4943G>A(p.Arg1648Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,610,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.63

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=0.020100325).
• BP6: Variant 19-50289626-G-A is Benign according to our data. Variant chr19-50289626-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 164200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50289626-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000217 (33/152188) while in subpopulation AMR AF= 0.00209 (32/15278). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.4943G>A	p.Arg1648Lys	missense_variant	35/43	ENST00000642316.2
MYH14	NM_001077186.2	c.4844G>A	p.Arg1615Lys	missense_variant	34/42
MYH14	NM_024729.4	c.4820G>A	p.Arg1607Lys	missense_variant	33/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.4943G>A	p.Arg1648Lys	missense_variant	35/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000268 AC: 65 AN: 242706 Hom.: 0 AF XY: 0.000197 AC XY: 26 AN XY: 131786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000487 AC: 71 AN: 1457998 Hom.: 0 Cov.: 32 AF XY: 0.0000400 AC XY: 29 AN XY: 724996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000181

ExAC AF: 0.000148 AC: 18

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	Invitae	Aug 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 12, 2016

p.Arg1648Lys in exon 35 of MYH14: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, wallaby has a lysine (Lys) at this position despite high nearby amino ac id conservation. It has been identified in 0.2% (16/7328) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Benign	0.85
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.020	T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	0.59	D;D;D;D
PrimateAI	Uncertain	0.77	T
Sift4G	Benign	1.0	T;T;T;T;.;T;T
Polyphen		0.0020	B;.;B;B;B;B;B
Vest4		0.18
MutPred		0.42		.;.;.;Gain of ubiquitination at R1607 (P = 0.0031);.;.;Gain of ubiquitination at R1607 (P = 0.0031);
MVP		0.53
MPC		0.16
ClinPred		0.12	T
GERP RS		2.9
Varity_R		0.10
gMVP		0.16

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: rs727503228; hg19: chr19-50792883; COSMIC: COSV51832106;