rs202225655

chr19-50280098-G-Achr19-50280098-G-C

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.4094G>A(p.Ser1365Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,610,186 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.00

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=0.011622041).
• BP6: Variant 19-50280098-G-A is Benign according to our data. Variant chr19-50280098-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 164188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50280098-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00125 (190/152336) while in subpopulation NFE AF= 0.00116 (79/68034). AF 95% confidence interval is 0.000954. There are 0 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.4094G>A	p.Ser1365Asn	missense_variant	31/43	ENST00000642316.2
MYH14	NM_001077186.2	c.3995G>A	p.Ser1332Asn	missense_variant	30/42
MYH14	NM_024729.4	c.3971G>A	p.Ser1324Asn	missense_variant	29/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.4094G>A	p.Ser1365Asn	missense_variant	31/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00146 AC: 353 AN: 242320 Hom.: 3 AF XY: 0.00138 AC XY: 181 AN XY: 131116

Gnomad AFR exome AF: 0.0000679

Gnomad AMR exome AF: 0.0000592

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00286

GnomAD4 exome AF: 0.00101 AC: 1476 AN: 1457850 Hom.: 7 Cov.: 32 AF XY: 0.000970 AC XY: 703 AN XY: 724722

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000453

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.000748

Gnomad4 OTH exome AF: 0.000863

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74486

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000833 Hom.: 0

Bravo AF: 0.000382

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000351 AC: 3

ExAC AF: 0.00148 AC: 179

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	May 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	MYH14: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 04, 2016

p.Ser1365Asn in exon 31 of MYH14: This variant is not expected to have clinical significance because it has been identified in 1.9% (73/3926) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202225655). -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.47	T
Sift4G	Benign	0.34	T;T;T;.;T;T;T
Polyphen		0.0040	B;B;B;B;B;B;.
Vest4		0.20
MVP		0.49
MPC		0.15
ClinPred		0.019	T
GERP RS		3.4
Varity_R		0.086
gMVP		0.18

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: rs202225655; hg19: chr19-50783355;