chr19-50286647-G-T

Position:

chr19-50286647-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001145809.2(MYH14):c.4705G>T(p.Ala1569Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000761 in 1,589,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 2.58

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:

MYH14 (HGNC:):

MYH14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030436993).

BP6

Variant 19-50286647-G-T is Benign according to our data. Variant chr19-50286647-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164199.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000374 (57/152374) while in subpopulation AMR AF= 0.00111 (17/15304). AF 95% confidence interval is 0.000707. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2 linkuse as main transcript	c.4705G>T	p.Ala1569Ser	missense_variant	34/43	ENST00000642316.2	NP_001139281.1	Q7Z406-2A1L2Z2B3KWH4
MYH14	NM_001077186.2 linkuse as main transcript	c.4606G>T	p.Ala1536Ser	missense_variant	33/42		NP_001070654.1	Q7Z406-6B3KWH4
MYH14	NM_024729.4 linkuse as main transcript	c.4582G>T	p.Ala1528Ser	missense_variant	32/41		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.4705G>T	p.Ala1569Ser	missense_variant	34/43		NM_001145809.2	ENSP00000493594.1		Q7Z406-2

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.0000934

AC:

AN:

203334

Hom.:

AF XY:

0.0000182

AC XY:

AN XY:

109888

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.000208

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000191

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1436822

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

712250

show subpopulations

Gnomad4 AFR exome

AF:

0.00127

Gnomad4 AMR exome

AF:

0.000325

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000151

GnomAD4 genome

AF:

0.000374

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.000646

ESP6500AA

AF:

0.000714

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000913

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 11, 2014

Variant classified as Uncertain Significance - Favor Benign. The Ala1569Ser vari ant in MYH14 has not been previously reported in individuals with hearing loss, but has been identified in 0.07% (3/4202) of African American chromosomes and 0. 01% (1/8436) European American chromosomes by the NHLBI Exome Sequencing Project , and in 1.0% (2/190) of Luhya (Kenyan) chromosomes and 0.8% (1/119) of Columbia n chromosomes by the 1000 Genomes Project (http://evs.gs.washington.edu/EVS/; db SNP rs145522874). Computational prediction tools and conservation analyses do no t provide strong support for or against an impact to the protein. In summary, wh ile the clinical significance of the Ala1569Ser variant is uncertain, its presen ce in several racially diverse populations at a range of frequencies (0.01% - 1. 0%) suggests a more likely benign role. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.4582G>T (p.A1528S) alteration is located in exon 32 (coding exon 31) of the MYH14 gene. This alteration results from a G to T substitution at nucleotide position 4582, causing the alanine (A) at amino acid position 1528 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;.;.;T;.;.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

.;T;T;T;.;T;.

M_CAP

Benign

0.035

MetaRNN

Benign

0.030

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.0013

MutationAssessor

Benign

1.7

.;.;.;L;.;.;L

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.94

.;.;N;.;.;.;.

REVEL

Benign

0.23

Sift

Benign

0.51

.;.;T;.;.;.;.

Sift4G

Benign

0.71

T;T;T;T;.;T;T

Polyphen

0.88

P;.;P;P;P;P;P

Vest4

0.38

MVP

0.68

MPC

0.44

ClinPred

0.049

GERP RS

4.5

Varity_R

0.081

gMVP

0.095

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

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