Genetic Variant NM_003802.3:c.5586C>A (chr17-10303277-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003802.3(MYH13):c.5586C>A(p.His1862Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1862Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH13
NM_003802.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0710

Publications

0 publications found

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:

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MYHAS links:

LOC107985004 (HGNC:):

LOC107985004 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11969265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH13	NM_003802.3 link	c.5586C>A	p.His1862Gln	missense_variant	Exon 39 of 41	ENST00000252172.9	NP_003793.2	Q9UKX3
LOC107985004	XR_001752791.3 link	n.95+11364G>T		intron_variant	Intron 1 of 4
LOC107985004	XR_007065617.1 link	n.95+11364G>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH13	ENST00000252172.9 link	c.5586C>A	p.His1862Gln	missense_variant	Exon 39 of 41	1	NM_003802.3	ENSP00000252172.4		Q9UKX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5586C>A (p.H1862Q) alteration is located in exon 39 (coding exon 37) of the MYH13 gene. This alteration results from a C to A substitution at nucleotide position 5586, causing the histidine (H) at amino acid position 1862 to be replaced by a glutamine (Q). 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

0.089

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.092

T;T;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.71

.;T;.

M_CAP

Benign

0.019

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.52

N;N;N

PhyloP100

0.071

PrimateAI

Benign

0.25

PROVEAN

Benign

0.62

.;.;N

REVEL

Benign

0.14

Sift

Benign

0.031

.;.;D

Sift4G

Uncertain

0.053

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.14

MutPred

0.40

Gain of ubiquitination at K1863 (P = 0.0702);Gain of ubiquitination at K1863 (P = 0.0702);Gain of ubiquitination at K1863 (P = 0.0702);

MVP

0.47

MPC

0.10

ClinPred

0.12

GERP RS

1.8

Varity_R

0.085

gMVP

0.088

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over