rs3744552

chr17-10400944-G-Achr17-10400944-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002472.3(MYH8):c.3270C>T(p.Ile1090=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,612,782 control chromosomes in the GnomAD database, including 259,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26507 hom., cov: 33)
  • Exomes 𝑓: 0.56 (232866 hom.)
• Consequence: MYH8 NM_002472.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.295

Genes affected

MYH8 (HGNC:7578): (myosin heavy chain 8) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is predominantly expressed in fetal skeletal muscle. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in trismus-pseudocamptodactyly syndrome. [provided by RefSeq, Sep 2009]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 17-10400944-G-A is Benign according to our data. Variant chr17-10400944-G-A is described in ClinVar as [Benign]. Clinvar id is 129674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10400944-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH8	NM_002472.3	c.3270C>T	p.Ile1090=	synonymous_variant	26/40	ENST00000403437.2
MYHAS	NR_125367.1	n.77-5204G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH8	ENST00000403437.2	c.3270C>T	p.Ile1090=	synonymous_variant	26/40	5	NM_002472.3	P1
	ENST00000399342.6	n.77-5204G>A		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.53-5204G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87907 AN: 151986 Hom.: 26487 Cov.: 33

Gnomad AFR AF: 0.699

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.603

GnomAD3 exomes AF: 0.494 AC: 123748 AN: 250446 Hom.: 33409 AF XY: 0.493 AC XY: 66736 AN XY: 135472

Gnomad AFR exome AF: 0.707

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.538

Gnomad EAS exome AF: 0.113

Gnomad SAS exome AF: 0.342

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.587

Gnomad OTH exome AF: 0.539

GnomAD4 exome AF: 0.555 AC: 810901 AN: 1460680 Hom.: 232866 Cov.: 47 AF XY: 0.550 AC XY: 399595 AN XY: 726656

Gnomad4 AFR exome AF: 0.708

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.536

Gnomad4 EAS exome AF: 0.150

Gnomad4 SAS exome AF: 0.348

Gnomad4 FIN exome AF: 0.528

Gnomad4 NFE exome AF: 0.589

Gnomad4 OTH exome AF: 0.543

GnomAD4 genome AF: 0.578 AC: 87977 AN: 152102 Hom.: 26507 Cov.: 33 AF XY: 0.565 AC XY: 41995 AN XY: 74336

Gnomad4 AFR AF: 0.699

Gnomad4 AMR AF: 0.506

Gnomad4 ASJ AF: 0.537

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.585

Gnomad4 OTH AF: 0.602

Alfa AF: 0.580 Hom.: 49411

Bravo AF: 0.587

Asia WGS AF: 0.276 AC: 963 AN: 3478

EpiCase AF: 0.597

EpiControl AF: 0.592

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hecht syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	5.3
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3744552; hg19: chr17-10304261; COSMIC: COSV67960036;