17-10390378-C-G

Position:

• chr17-10390378-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002472.3(MYH8):​c.*76G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 1,555,640 control chromosomes in the GnomAD database, including 1,601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (79 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1522 hom.)
• Consequence: MYH8 NM_002472.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.614

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-10390378-C-G is Benign according to our data. Variant chr17-10390378-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 321619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH8	NM_002472.3	c.*76G>C		3_prime_UTR_variant	40/40	ENST00000403437.2	NP_002463.2
MYHAS	NR_125367.1	n.76+7171C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH8	ENST00000403437.2	c.*76G>C		3_prime_UTR_variant	40/40	5	NM_002472.3	ENSP00000384330	P1
	ENST00000399342.6	n.76+7171C>G		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.52+7171C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4435 AN: 152146 Hom.: 79 Cov.: 33

Gnomad AFR AF: 0.00842

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0187

GnomAD4 exome AF: 0.0427 AC: 59959 AN: 1403376 Hom.: 1522 Cov.: 24 AF XY: 0.0432 AC XY: 30305 AN XY: 701620

Gnomad4 AFR exome AF: 0.00617

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.0152

Gnomad4 EAS exome AF: 0.00969

Gnomad4 SAS exome AF: 0.0526

Gnomad4 FIN exome AF: 0.0366

Gnomad4 NFE exome AF: 0.0469

Gnomad4 OTH exome AF: 0.0360

GnomAD4 genome AF: 0.0291 AC: 4436 AN: 152264 Hom.: 79 Cov.: 33 AF XY: 0.0290 AC XY: 2157 AN XY: 74444

Gnomad4 AFR AF: 0.00840

Gnomad4 AMR AF: 0.0191

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.0118

Gnomad4 SAS AF: 0.0510

Gnomad4 FIN AF: 0.0405

Gnomad4 NFE AF: 0.0434

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0329 Hom.: 8

Bravo AF: 0.0253

Asia WGS AF: 0.0440 AC: 152 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hecht syndrome Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.7
DANN	Benign	0.71

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: rs3744551; hg19: chr17-10293695;