17-10459429-A-G

Variant names:

• chr17-10459429-A-G
• rs2058099
• NM_017533.2:c.1417-8T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017533.2(MYH4):​c.1417-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,613,820 control chromosomes in the GnomAD database, including 165,018 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (15152 hom., cov: 31)
  • Exomes 𝑓: 0.44 (149866 hom.)
• Consequence: MYH4 NM_017533.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001887
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.181
• Publications: 10 publications found

Genes affected

MYH4 (HGNC:7574): (myosin heavy chain 4) Enables double-stranded RNA binding activity. Involved in muscle contraction. Located in myofibril. [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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017533.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH4	NM_017533.2	MANE Select	c.1417-8T>C		splice_region intron	N/A	NP_060003.2
	MYHAS	NR_125367.1		n.167+53191A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH4	ENST00000255381.2	TSL:1 MANE Select	c.1417-8T>C		splice_region intron	N/A	ENSP00000255381.2
	MYHAS	ENST00000399342.6	TSL:3	n.206+53152A>G		intron	N/A
	MYHAS	ENST00000581304.2	TSL:3	n.143+53191A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65923 AN: 151836 Hom.: 15145 Cov.: 31

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.404

GnomAD2 exomes AF: 0.502 AC: 126288 AN: 251454 AF XY: 0.501

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.611

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.874

Gnomad FIN exome AF: 0.478

Gnomad NFE exome AF: 0.410

Gnomad OTH exome AF: 0.460

GnomAD4 exome AF: 0.442 AC: 646648 AN: 1461866 Hom.: 149866 Cov.: 66 AF XY: 0.447 AC XY: 324779 AN XY: 727234

African (AFR) AF: 0.347 AC: 11630 AN: 33480

American (AMR) AF: 0.594 AC: 26571 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12071 AN: 26136

East Asian (EAS) AF: 0.843 AC: 33466 AN: 39698

South Asian (SAS) AF: 0.620 AC: 53487 AN: 86258

European-Finnish (FIN) AF: 0.467 AC: 24928 AN: 53420

Middle Eastern (MID) AF: 0.446 AC: 2570 AN: 5768

European-Non Finnish (NFE) AF: 0.409 AC: 454414 AN: 1111986

Other (OTH) AF: 0.456 AC: 27511 AN: 60396

GnomAD4 genome AF: 0.434 AC: 65970 AN: 151954 Hom.: 15152 Cov.: 31 AF XY: 0.446 AC XY: 33160 AN XY: 74284

African (AFR) AF: 0.353 AC: 14607 AN: 41404

American (AMR) AF: 0.501 AC: 7654 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1600 AN: 3472

East Asian (EAS) AF: 0.856 AC: 4422 AN: 5168

South Asian (SAS) AF: 0.638 AC: 3063 AN: 4800

European-Finnish (FIN) AF: 0.481 AC: 5083 AN: 10564

Middle Eastern (MID) AF: 0.445 AC: 130 AN: 292

European-Non Finnish (NFE) AF: 0.414 AC: 28123 AN: 67950

Other (OTH) AF: 0.404 AC: 851 AN: 2108

Alfa AF: 0.412 Hom.: 5768

Bravo AF: 0.429

Asia WGS AF: 0.687 AC: 2388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.44
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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: rs2058099; hg19: chr17-10362746; COSMIC: COSV55114966;