rs55645295

Positions:

• chr19-50226918-A-G

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.826A>G​(p.Ile276Val) variant causes a missense change. The variant allele was found at a frequency of 0.000778 in 1,613,758 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.04

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012801915).
• BP6: Variant 19-50226918-A-G is Benign according to our data. Variant chr19-50226918-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 178413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50226918-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00412 (627/152144) while in subpopulation AFR AF= 0.0146 (606/41492). AF 95% confidence interval is 0.0136. There are 3 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 627 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.826A>G	p.Ile276Val	missense_variant	8/43	ENST00000642316.2
MYH14	NM_001077186.2	c.826A>G	p.Ile276Val	missense_variant	8/42
MYH14	NM_024729.4	c.802A>G	p.Ile268Val	missense_variant	7/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.826A>G	p.Ile276Val	missense_variant	8/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 627 AN: 152026 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

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: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00107 AC: 270 AN: 251200 Hom.: 1 AF XY: 0.000729 AC XY: 99 AN XY: 135790

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.00116

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: 0.0000616

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000430 AC: 629 AN: 1461614 Hom.: 5 Cov.: 32 AF XY: 0.000373 AC XY: 271 AN XY: 727130

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.00123

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: 0.0000144

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00412 AC: 627 AN: 152144 Hom.: 3 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74384

Gnomad4 AFR AF: 0.0146

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.00467

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Ile276Val in Exon 08 of MYH14: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (48/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs55645295). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	.;.;T;.;T;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	.;D;D;.;D;D;.
MetaRNN	Benign	0.013	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.6	.;.;L;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.93	.;N;N;.;.;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.075	.;T;T;.;.;.;.
Sift4G	Benign	0.10	T;T;T;.;T;T;T
Polyphen		0.88	P;P;P;P;.;P;P
Vest4		0.58
MVP		0.62
MPC		0.52
ClinPred		0.031	T
GERP RS		3.9
Varity_R		0.096
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55645295; hg19: chr19-50730175;