19-50301881-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145809.2(MYH14):c.5678+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.837 in 1,601,276 control chromosomes in the GnomAD database, including 562,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47548 hom., cov: 31)
  • Exomes 𝑓: 0.84 (515434 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.368

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 (BayesDel_noAF=-0.96).
• BP6: Variant 19-50301881-C-T is Benign according to our data. Variant chr19-50301881-C-T is described in ClinVar as [Benign]. Clinvar id is 226747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50301881-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.5678+12C>T		intron_variant		ENST00000642316.2
MYH14	NM_001077186.2	c.5579+12C>T		intron_variant
MYH14	NM_024729.4	c.5555+12C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.5678+12C>T		intron_variant			NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119165 AN: 151926 Hom.: 47533 Cov.: 31

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.886

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.856

Gnomad OTH AF: 0.792

GnomAD3 exomes AF: 0.829 AC: 191380 AN: 230798 Hom.: 79740 AF XY: 0.829 AC XY: 103879 AN XY: 125316

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.862

Gnomad ASJ exome AF: 0.889

Gnomad EAS exome AF: 0.819

Gnomad SAS exome AF: 0.775

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.855

Gnomad OTH exome AF: 0.843

GnomAD4 exome AF: 0.842 AC: 1220279 AN: 1449232 Hom.: 515434 Cov.: 32 AF XY: 0.840 AC XY: 605299 AN XY: 720192

Gnomad4 AFR exome AF: 0.625

Gnomad4 AMR exome AF: 0.857

Gnomad4 ASJ exome AF: 0.895

Gnomad4 EAS exome AF: 0.764

Gnomad4 SAS exome AF: 0.779

Gnomad4 FIN exome AF: 0.841

Gnomad4 NFE exome AF: 0.855

Gnomad4 OTH exome AF: 0.829

GnomAD4 genome AF: 0.784 AC: 119218 AN: 152044 Hom.: 47548 Cov.: 31 AF XY: 0.783 AC XY: 58199 AN XY: 74326

Gnomad4 AFR AF: 0.634

Gnomad4 AMR AF: 0.819

Gnomad4 ASJ AF: 0.886

Gnomad4 EAS AF: 0.809

Gnomad4 SAS AF: 0.776

Gnomad4 FIN AF: 0.830

Gnomad4 NFE AF: 0.856

Gnomad4 OTH AF: 0.791

Alfa AF: 0.840 Hom.: 74850

Bravo AF: 0.779

Asia WGS AF: 0.805 AC: 2799 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	5678+12C>T in Intron 40 of MYH14: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 33.3% (1157/3478) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs3826772). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal dominant nonsyndromic hearing loss 4A Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.014
Dann	Benign	0.53

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: rs3826772; hg19: chr19-50805138;