17-10303277-G-T

Variant names:

• chr17-10303277-G-T
• NM_003802.3:c.5586C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 15/21 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. H1862R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH13 NM_003802.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0710

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]

ENSG00000273388 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 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	c.5586C>A	p.His1862Gln	missense_variant	Exon 39 of 41	ENST00000252172.9	NP_003793.2
LOC107985004	XR_001752791.3	n.95+11364G>T		intron_variant	Intron 1 of 4
LOC107985004	XR_007065617.1	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	c.5586C>A	p.His1862Gln	missense_variant	Exon 39 of 41	1	NM_003802.3	ENSP00000252172.4
MYH13	ENST00000621918.1	c.5586C>A	p.His1862Gln	missense_variant	Exon 37 of 39	1		ENSP00000480864.1
MYH13	ENST00000418404.8	c.5586C>A	p.His1862Gln	missense_variant	Exon 38 of 40	5		ENSP00000404570.3
ENSG00000273388	ENST00000609088.1	n.94+11364G>T		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
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	N
LIST_S2	Benign	0.71	.;T;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.52	N;N;N
PrimateAI	Benign	0.25	T
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	T
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-10206594;