chr17-10630259-A-G

Variant names:

• chr17-10630259-A-G
• rs73976869
• NM_002470.4:c.5457+29T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000583535.6(MYH3):​c.5457+29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,581,590 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (92 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (80 hom.)
• Consequence: MYH3 ENST00000583535.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.73
• Publications: 0 publications found

Genes affected

MYH3 (HGNC:7573): (myosin heavy chain 3) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-10630259-A-G is Benign according to our data. Variant chr17-10630259-A-G is described in ClinVar as Benign. ClinVar VariationId is 258697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0697 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000583535.6. 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
	MYH3	NM_002470.4	MANE Select	c.5457+29T>C		intron	N/A	NP_002461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.5457+29T>C		intron	N/A	ENSP00000464317.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+16382A>G		intron	N/A
	MYHAS	ENST00000584139.2	TSL:3	n.1041+16382A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3007 AN: 119576 Hom.: 91 Cov.: 33

Gnomad AFR AF: 0.0722

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00193

Gnomad EAS AF: 0.00345

Gnomad SAS AF: 0.000802

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00787

Gnomad NFE AF: 0.000565

Gnomad OTH AF: 0.0152

GnomAD2 exomes AF: 0.00588 AC: 1474 AN: 250616 AF XY: 0.00419

Gnomad AFR exome AF: 0.0724

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00220 AC: 3222 AN: 1461884 Hom.: 80 Cov.: 35 AF XY: 0.00188 AC XY: 1368 AN XY: 727242

African (AFR) AF: 0.0692 AC: 2317 AN: 33480

American (AMR) AF: 0.00619 AC: 277 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26136

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39698

South Asian (SAS) AF: 0.000556 AC: 48 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.000179 AC: 199 AN: 1112006

Other (OTH) AF: 0.00490 AC: 296 AN: 60394

GnomAD4 genome AF: 0.0252 AC: 3013 AN: 119706 Hom.: 92 Cov.: 33 AF XY: 0.0237 AC XY: 1378 AN XY: 58096

African (AFR) AF: 0.0719 AC: 2800 AN: 38930

American (AMR) AF: 0.0114 AC: 128 AN: 11266

Ashkenazi Jewish (ASJ) AF: 0.00193 AC: 5 AN: 2592

East Asian (EAS) AF: 0.00346 AC: 15 AN: 4338

South Asian (SAS) AF: 0.000802 AC: 3 AN: 3742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6762

Middle Eastern (MID) AF: 0.00855 AC: 2 AN: 234

European-Non Finnish (NFE) AF: 0.000565 AC: 28 AN: 49578

Other (OTH) AF: 0.0201 AC: 32 AN: 1596

Alfa AF: 0.00867 Hom.: 9

Bravo AF: 0.0220

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.43
DANN	Benign	0.30
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs73976869; hg19: chr17-10533576;