19-50223349-C-T

Position:

chr19-50223349-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

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:2B:1

Conservation

PhyloP100: -0.533

Variant links:

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]

MYH14 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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.

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2 linkuse as main transcript	c.693C>T	p.Pro231Pro	splice_region_variant, synonymous_variant	5/43	ENST00000642316.2	NP_001139281.1	Q7Z406-2A1L2Z2B3KWH4
MYH14	NM_001077186.2 linkuse as main transcript	c.693C>T	p.Pro231Pro	splice_region_variant, synonymous_variant	5/42		NP_001070654.1	Q7Z406-6B3KWH4
MYH14	NM_024729.4 linkuse as main transcript	c.693C>T	p.Pro231Pro	splice_region_variant, synonymous_variant	5/41		NP_079005.3	Q7Z406-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2 linkuse as main transcript	c.693C>T	p.Pro231Pro	splice_region_variant, synonymous_variant	5/43		NM_001145809.2	ENSP00000493594.1		Q7Z406-2

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

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:

AN:

172986

Hom.:

AF XY:

0.000130

AC XY:

AN XY:

92298

show subpopulations

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.:

Cov.:

AF XY:

0.0000773

AC XY:

AN XY:

698150

show subpopulations

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:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74378

show subpopulations

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.:

Bravo

AF:

0.0000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2022	ClinVar contains an entry for this variant (Variation ID: 505603). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with MYH14-related conditions. 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	MYH14: BP4, BP7 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 24, 2017

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over