17-10306943-G-T

Variant names:

• chr17-10306943-G-T
• rs192011217
• NM_003802.3:c.5291C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003802.3(MYH13):​c.5291C>A​(p.Thr1764Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1764M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYH13 NM_003802.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95
• Publications: 0 publications found

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]

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]

LOC107985004 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003802.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH13	NM_003802.3	MANE Select	c.5291C>A	p.Thr1764Lys	missense	Exon 36 of 41	NP_003793.2	Q9UKX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH13	ENST00000252172.9	TSL:1 MANE Select	c.5291C>A	p.Thr1764Lys	missense	Exon 36 of 41	ENSP00000252172.4	Q9UKX3
	MYH13	ENST00000621918.1	TSL:1	c.5291C>A	p.Thr1764Lys	missense	Exon 34 of 39	ENSP00000480864.1	Q9UKX3
	MYH13	ENST00000418404.8	TSL:5	c.5291C>A	p.Thr1764Lys	missense	Exon 35 of 40	ENSP00000404570.3	Q9UKX3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461174 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726858

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5364

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111892

Other (OTH) AF: 0.0000166 AC: 1 AN: 60320

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.022	D
Sift4G	Benign	0.18	T
Polyphen		0.96	D
Vest4		0.72
MutPred		0.57		Loss of phosphorylation at T1764 (P = 0.0171)
MVP		0.88
MPC		0.28
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.53
gMVP		0.79

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

Other links and lift over

dbSNP: rs192011217; hg19: chr17-10210260; COSMIC: COSV104990901;