rs1396600

Variant names:

• chr17-10646069-G-A
• rs1396600
• NM_002470.4:c.899-37C>T

Variant summary

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

The NM_002470.4(MYH3):​c.899-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,585,094 control chromosomes in the GnomAD database, including 252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (112 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (140 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.658
• Publications: 1 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=-0.8).
• BP6: Variant 17-10646069-G-A is Benign according to our data. Variant chr17-10646069-G-A is described in ClinVar as Benign. ClinVar VariationId is 258705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.899-37C>T		intron_variant	Intron 10 of 40	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.899-37C>T		intron_variant	Intron 10 of 40		XP_011522172.1
MYH3	XM_011523871.3	c.899-37C>T		intron_variant	Intron 10 of 40		XP_011522173.1
MYH3	XM_047436127.1	c.899-37C>T		intron_variant	Intron 12 of 42		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.899-37C>T		intron_variant	Intron 10 of 40	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2	n.705+32192G>A		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1041+32192G>A		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3330 AN: 152090 Hom.: 112 Cov.: 31

Gnomad AFR AF: 0.0770

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00601 AC: 1465 AN: 243700 AF XY: 0.00423

Gnomad AFR exome AF: 0.0823

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00233 AC: 3333 AN: 1432886 Hom.: 140 Cov.: 29 AF XY: 0.00198 AC XY: 1413 AN XY: 714304

African (AFR) AF: 0.0799 AC: 2621 AN: 32798

American (AMR) AF: 0.00381 AC: 168 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.000259 AC: 22 AN: 85046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00454 AC: 26 AN: 5730

European-Non Finnish (NFE) AF: 0.000143 AC: 155 AN: 1087152

Other (OTH) AF: 0.00574 AC: 341 AN: 59426

GnomAD4 genome AF: 0.0219 AC: 3327 AN: 152208 Hom.: 112 Cov.: 31 AF XY: 0.0205 AC XY: 1529 AN XY: 74434

African (AFR) AF: 0.0767 AC: 3184 AN: 41520

American (AMR) AF: 0.00582 AC: 89 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68020

Other (OTH) AF: 0.0114 AC: 24 AN: 2110

Alfa AF: 0.0152 Hom.: 36

Bravo AF: 0.0252

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 11, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.3
DANN	Benign	0.76
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1396600; hg19: chr17-10549386;