Genetic Variant NM_003802.3:c.5233G>A (chr17-10307001-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003802.3(MYH13):c.5233G>A(p.Val1745Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MYH13
NM_003802.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.169

Variant links:

Genes affected

MYH13 (HGNC:7571): (myosin heavy chain 13) Predicted to enable microfilament motor activity. Predicted to be involved in muscle contraction. Predicted to act upstream of or within cellular response to starvation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

MYH13 links:

ENSG00000273388 (HGNC:):

ENSG00000273388 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10708052).

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH13	NM_003802.3 link	c.5233G>A	p.Val1745Met	missense_variant	Exon 36 of 41	ENST00000252172.9	NP_003793.2	Q9UKX3
LOC107985004	XR_001752791.3 link	n.96-10497C>T		intron_variant	Intron 1 of 4
LOC107985004	XR_007065617.1 link	n.96-10497C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH13	ENST00000252172.9 link	c.5233G>A	p.Val1745Met	missense_variant	Exon 36 of 41	1	NM_003802.3	ENSP00000252172.4	Q9UKX3
MYH13	ENST00000621918.1 link	c.5233G>A	p.Val1745Met	missense_variant	Exon 34 of 39	1		ENSP00000480864.1	Q9UKX3
MYH13	ENST00000418404.8 link	c.5233G>A	p.Val1745Met	missense_variant	Exon 35 of 40	5		ENSP00000404570.3	Q9UKX3
ENSG00000273388	ENST00000609088.1 link	n.95-10497C>T		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5233G>A (p.V1745M) alteration is located in exon 36 (coding exon 34) of the MYH13 gene. This alteration results from a G to A substitution at nucleotide position 5233, causing the valine (V) at amino acid position 1745 to be replaced by a methionine (M). 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

0.087

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.75

.;T;.

M_CAP

Benign

0.036

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.89

.;.;N

REVEL

Benign

0.16

Sift

Benign

0.24

.;.;T

Sift4G

Benign

0.088

T;T;T

Polyphen

0.012

B;B;B

Vest4

0.21

MutPred

0.42

Gain of phosphorylation at S1748 (P = 0.1854);Gain of phosphorylation at S1748 (P = 0.1854);Gain of phosphorylation at S1748 (P = 0.1854);

MVP

0.55

MPC

0.10

ClinPred

0.42

GERP RS

3.1

Varity_R

0.061

gMVP

0.76

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