17-10306599-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4 BP6_Moderate BS2

The NM_003802.3(MYH13):c.5326G>A(p.Glu1776Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,614,100 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (3 hom.)
• Consequence: MYH13 NM_003802.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.13

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.38028687).
• BP6: Variant 17-10306599-C-T is Benign according to our data. Variant chr17-10306599-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3034936.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH13	NM_003802.3	c.5326G>A	p.Glu1776Lys	missense_variant	37/41	ENST00000252172.9
LOC107985004	XR_007065617.1	n.96-10899C>T		intron_variant, non_coding_transcript_variant
LOC107985004	XR_001752791.3	n.96-10899C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH13	ENST00000252172.9	c.5326G>A	p.Glu1776Lys	missense_variant	37/41	1	NM_003802.3	P1
MYH13	ENST00000621918.1	c.5326G>A	p.Glu1776Lys	missense_variant	35/39	1		P1
	ENST00000609088.1	n.95-10899C>T		intron_variant, non_coding_transcript_variant		4
MYH13	ENST00000418404.8	c.5326G>A	p.Glu1776Lys	missense_variant	36/40	5		P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 251476 Hom.: 2 AF XY: 0.000316 AC XY: 43 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1461852 Hom.: 3 Cov.: 32 AF XY: 0.000180 AC XY: 131 AN XY: 727228

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: 0.00194

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74426

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000490 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MYH13-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.83
MutPred		0.78		Gain of MoRF binding (P = 0.0077);Gain of MoRF binding (P = 0.0077);Gain of MoRF binding (P = 0.0077);
MVP		0.95
MPC		0.53
ClinPred		0.39	T
GERP RS		4.3
Varity_R		0.49
gMVP		0.94

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

Other links and lift over

dbSNP: rs574010739; hg19: chr17-10209916;