17-10459429-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ENSG00000272736 (HGNC:):

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH4	NM_017533.2	c.1417-8T>C		splice_region_variant, intron_variant	Intron 14 of 39	ENST00000255381.2	NP_060003.2
MYH4	XM_017024676.2	c.1417-8T>C		splice_region_variant, intron_variant	Intron 12 of 37		XP_016880165.1
MYHAS	NR_125367.1	n.167+53191A>G		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH4	ENST00000255381.2	c.1417-8T>C		splice_region_variant, intron_variant	Intron 14 of 39	1	NM_017533.2	ENSP00000255381.2
ENSG00000272736	ENST00000399342.6	n.206+53152A>G		intron_variant	Intron 2 of 3	3
ENSG00000272736	ENST00000581304.1	n.143+53191A>G		intron_variant	Intron 2 of 3	3
MYHAS	ENST00000587182.2	n.155+53191A>G		intron_variant	Intron 2 of 10	5

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

GnomAD3 exomes AF: 0.502 AC: 126288 AN: 251454 Hom.: 34246 AF XY: 0.501 AC XY: 68145 AN XY: 135896

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 SAS exome AF: 0.622

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

Gnomad4 AFR exome AF: 0.347

Gnomad4 AMR exome AF: 0.594

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.843

Gnomad4 SAS exome AF: 0.620

Gnomad4 FIN exome AF: 0.467

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.456

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

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.856

Gnomad4 SAS AF: 0.638

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.414

Gnomad4 OTH AF: 0.404

Alfa AF: 0.413 Hom.: 5725

Bravo AF: 0.429

Asia WGS AF: 0.687 AC: 2388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs2058099; hg19: chr17-10362746; COSMIC: COSV55114966;