17-10459429-A-G

Position:

• chr17-10459429-A-G

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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, 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]

(HGNC:):

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/exons	MANE	UniProt
MYH4	NM_017533.2	c.1417-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000255381.2
MYHAS	NR_125367.1	n.167+53191A>G		intron_variant, non_coding_transcript_variant
MYH4	XM_017024676.2	c.1417-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH4	ENST00000255381.2	c.1417-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_017533.2	P1
	ENST00000399342.6	n.206+53152A>G		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.143+53191A>G		intron_variant, non_coding_transcript_variant		3

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;