rs200176028

chr19-50247137-C-T

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.1329+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,583,854 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (14 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.01

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=-0.91).
• BP6: Variant 19-50247137-C-T is Benign according to our data. Variant chr19-50247137-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50247137-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00224 (341/152284) while in subpopulation NFE AF= 0.00295 (201/68022). AF 95% confidence interval is 0.00262. There are 0 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 339 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.1329+15C>T		intron_variant		ENST00000642316.2
MYH14	NM_001077186.2	c.1329+15C>T		intron_variant
MYH14	NM_024729.4	c.1305+15C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.1329+15C>T		intron_variant			NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00271 AC: 645 AN: 237772 Hom.: 1 AF XY: 0.00272 AC XY: 352 AN XY: 129224

Gnomad AFR exome AF: 0.000572

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000285

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.000872

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.00342 AC: 4891 AN: 1431570 Hom.: 14 Cov.: 25 AF XY: 0.00335 AC XY: 2385 AN XY: 712962

Gnomad4 AFR exome AF: 0.000638

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.000254

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.000779

Gnomad4 NFE exome AF: 0.00367

Gnomad4 OTH exome AF: 0.00393

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74462

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00295

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00355 Hom.: 0

Bravo AF: 0.00257

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	MYH14: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

1329+15C>T in Intron 12 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 0.4% (24/6830) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS). -

Autosomal dominant nonsyndromic hearing loss 4A;C3280556:Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.34
Dann	Benign	0.51

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: rs200176028; hg19: chr19-50750394;