19-50223349-C-T

Variant names:

• chr19-50223349-C-T
• rs373744231
• NM_001145809.2:c.693C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001145809.2(MYH14):​c.693C>T​(p.Pro231Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000844 in 1,563,996 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: MYH14 NM_001145809.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002260
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.533

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-50223349-C-T is Benign according to our data. Variant chr19-50223349-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505603.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=-0.533 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000854 (13/152238) while in subpopulation SAS AF= 0.000207 (1/4832). AF 95% confidence interval is 0.000068. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.693C>T	p.Pro231Pro	splice_region_variant, synonymous_variant	Exon 5 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.693C>T	p.Pro231Pro	splice_region_variant, synonymous_variant	Exon 5 of 42		NP_001070654.1
MYH14	NM_024729.4	c.693C>T	p.Pro231Pro	splice_region_variant, synonymous_variant	Exon 5 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.693C>T	p.Pro231Pro	splice_region_variant, synonymous_variant	Exon 5 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.0000925 AC: 16 AN: 172986 Hom.: 0 AF XY: 0.000130 AC XY: 12 AN XY: 92298

Gnomad AFR exome AF: 0.000214

Gnomad AMR exome AF: 0.0000778

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000830

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.0000843 AC: 119 AN: 1411758 Hom.: 0 Cov.: 32 AF XY: 0.0000773 AC XY: 54 AN XY: 698150

Gnomad4 AFR exome AF: 0.0000623

Gnomad4 AMR exome AF: 0.0000812

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000866

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000921

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74378

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.0000447 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jun 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs373744231, gnomAD 0.02%). This sequence change affects codon 231 of the MYH14 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYH14 protein. It affects a nucleotide within the consensus splice site. This variant has not been reported in the literature in individuals affected with MYH14-related conditions. ClinVar contains an entry for this variant (Variation ID: 505603). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH14: BP4, BP7 -

not specified Uncertain:1

Jan 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Pro231Pro var iant in MYH14 has not been previously reported in individuals with hearing loss, but has been identified in 8/69014 European chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373744231). Altho ugh this variant has been seen in the general population, its frequency is not h igh enough to rule out a pathogenic role. This variant is located in the last ba se of the exon, which is part of the 5? splice region. Computational tools do no t predict altered splicing; however, this information is not predictive enough t o rule out pathogenicity. Nevertheless, this genomic position is not well conser ved in mammals or evolutionarily distant species and >10 mammals have a thymine residue at this position, supporting that this change may be tolerated. In summa ry, while the clinical significance of the p.Pro231Pro variant is uncertain, the se data suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.5
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
dbscSNV1_RF	Benign	0.064
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: rs373744231; hg19: chr19-50726606;