chr17-10421663-C-T

Position:

• chr17-10421663-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002472.3(MYH8):​c.-31G>A variant causes a splice region, 5 prime UTR change. The variant allele was found at a frequency of 0.322 in 152,014 control chromosomes in the GnomAD database, including 9,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9051 hom., cov: 32)
  • Exomes 𝑓: 0.33 (0 hom.)
• Consequence: MYH8 NM_002472.3 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.49

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 -16 ACMG points.

• BP6: Variant 17-10421663-C-T is Benign according to our data. Variant chr17-10421663-C-T is described in ClinVar as [Benign]. Clinvar id is 321659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH8	NM_002472.3	c.-31G>A		splice_region_variant, 5_prime_UTR_variant	2/40	ENST00000403437.2	NP_002463.2
MYHAS	NR_125367.1	n.167+15425C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH8	ENST00000403437.2	c.-31G>A		splice_region_variant, 5_prime_UTR_variant	2/40	5	NM_002472.3	ENSP00000384330	P1
	ENST00000399342.6	n.206+15386C>T		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.143+15425C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48935 AN: 151890 Hom.: 9052 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.826

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.299

GnomAD4 exome AF: 0.333 AC: 2 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.333 AC XY: 2 AN XY: 6

Gnomad4 NFE exome AF: 0.333

GnomAD4 genome AF: 0.322 AC: 48959 AN: 152008 Hom.: 9051 Cov.: 32 AF XY: 0.335 AC XY: 24880 AN XY: 74310

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.315

Gnomad4 EAS AF: 0.826

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.383

Gnomad4 NFE AF: 0.303

Gnomad4 OTH AF: 0.300

Alfa AF: 0.324 Hom.: 17127

Bravo AF: 0.319

Asia WGS AF: 0.611 AC: 2119 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hecht syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.10		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: rs2277648; hg19: chr17-10324980;