rs587776357

Positions:

• chr19-50275988-C-T
• chr19-50275988-C-A

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.3468-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,611,082 control chromosomes in the GnomAD database, including 503 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (42 hom., cov: 33)
  • Exomes 𝑓: 0.023 (461 hom.)
• Consequence: MYH14 NM_001145809.2 splice_region, intron
• Scores: Splicing: ADA: 0.0006063
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.76

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=-0.62).
• BP6: Variant 19-50275988-C-T is Benign according to our data. Variant chr19-50275988-C-T is described in ClinVar as [Benign]. Clinvar id is 44066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50275988-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2604/152318) while in subpopulation NFE AF= 0.0261 (1778/68026). AF 95% confidence interval is 0.0251. There are 42 homozygotes in gnomad4. There are 1150 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2604 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.3468-3C>T		splice_region_variant, intron_variant		ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.3369-3C>T		splice_region_variant, intron_variant			NP_001070654.1
MYH14	NM_024729.4	c.3345-3C>T		splice_region_variant, intron_variant			NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.3468-3C>T		splice_region_variant, intron_variant			NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2605 AN: 152200 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0177 AC: 4276 AN: 242056 Hom.: 59 AF XY: 0.0181 AC XY: 2398 AN XY: 132318

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.0395

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00837

Gnomad FIN exome AF: 0.00645

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0231 AC: 33626 AN: 1458764 Hom.: 461 Cov.: 31 AF XY: 0.0226 AC XY: 16368 AN XY: 725514

Gnomad4 AFR exome AF: 0.00362

Gnomad4 AMR exome AF: 0.0162

Gnomad4 ASJ exome AF: 0.0398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00865

Gnomad4 FIN exome AF: 0.00822

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0171 AC: 2604 AN: 152318 Hom.: 42 Cov.: 33 AF XY: 0.0154 AC XY: 1150 AN XY: 74482

Gnomad4 AFR AF: 0.00488

Gnomad4 AMR AF: 0.0193

Gnomad4 ASJ AF: 0.0415

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.0261

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0243 Hom.: 29

Bravo AF: 0.0179

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

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	Apr 30, 2012	3468-3C>T in Intron 27 of MYH14: This variant is not expected to have clinical s ignificance because it has been identified in 2.5% (165/6628) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs78192108). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1 Other:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	Genomic Research Center, Shahid Beheshti University of Medical Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00061
dbscSNV1_RF	Benign	0.036
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: rs78192108; hg19: chr19-50779245;