19-50252726-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001145809.2(MYH14):c.1918C>T(p.Arg640Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,595,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R640Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.99

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030691683).
• BP6: Variant 19-50252726-C-T is Benign according to our data. Variant chr19-50252726-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178416.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr19-50252726-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000236 (36/152280) while in subpopulation SAS AF= 0.00124 (6/4820). AF 95% confidence interval is 0.000813. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.1918C>T	p.Arg640Trp	missense_variant	16/43	ENST00000642316.2
MYH14	NM_001077186.2	c.1918C>T	p.Arg640Trp	missense_variant	16/42
MYH14	NM_024729.4	c.1894C>T	p.Arg632Trp	missense_variant	15/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.1918C>T	p.Arg640Trp	missense_variant	16/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000449 AC: 98 AN: 218474 Hom.: 1 AF XY: 0.000568 AC XY: 67 AN XY: 117932

Gnomad AFR exome AF: 0.000159

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00284

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000819

Gnomad OTH exome AF: 0.000362

GnomAD4 exome AF: 0.000200 AC: 288 AN: 1443290 Hom.: 2 Cov.: 30 AF XY: 0.000242 AC XY: 173 AN XY: 716216

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.000310

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000770

Gnomad4 OTH exome AF: 0.000251

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74454

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000344 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.000231 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000421 AC: 51

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 03, 2018

The p.Arg640Trp variant in MYH14 has been previously reported by our laboratory in 1 individual with hearing loss, and it has also been identified in 0.28% (75/ 26920) of South Asian chromosomes including 1 homozygote by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg640Trp variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. -

MYH14-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2019

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	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.69	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.031	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	0.58	D;D;D;D
PrimateAI	Benign	0.42	T
Sift4G	Uncertain	0.0060	D;D;D;.;D;D;D
Polyphen		0.070	B;B;B;B;.;B;B
Vest4		0.50
MVP		0.77
MPC		0.48
ClinPred		0.048	T
GERP RS		2.0
Varity_R		0.17
gMVP		0.59

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: rs376267080; hg19: chr19-50755983; COSMIC: COSV51816114; COSMIC: COSV51816114;