chr17-10638198-C-T

Variant names:

• chr17-10638198-C-T
• rs2285477
• NM_002470.4:c.3574G>A

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.3574G>A​(p.Ala1192Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 1,613,298 control chromosomes in the GnomAD database, including 460,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1192M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.69 (37317 hom., cov: 27)
  • Exomes 𝑓: 0.75 (422721 hom.)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.761
• Publications: 36 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 (MetaRNN=8.30933E-6).
• BP6: Variant 17-10638198-C-T is Benign according to our data. Variant chr17-10638198-C-T is described in ClinVar as Benign. ClinVar VariationId is 129658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002470.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.3574G>A	p.Ala1192Thr	missense	Exon 27 of 41	NP_002461.2	P11055

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.3574G>A	p.Ala1192Thr	missense	Exon 27 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.3574G>A	p.Ala1192Thr	missense	Exon 26 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+24321C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.693 AC: 104795 AN: 151322 Hom.: 37289 Cov.: 27

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.796

Gnomad OTH AF: 0.689

GnomAD2 exomes AF: 0.687 AC: 172652 AN: 251444 AF XY: 0.695

Gnomad AFR exome AF: 0.568

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.755

Gnomad EAS exome AF: 0.374

Gnomad FIN exome AF: 0.749

Gnomad NFE exome AF: 0.789

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.755 AC: 1103404 AN: 1461860 Hom.: 422721 Cov.: 109 AF XY: 0.753 AC XY: 547392 AN XY: 727230

African (AFR) AF: 0.553 AC: 18512 AN: 33480

American (AMR) AF: 0.568 AC: 25394 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 19682 AN: 26136

East Asian (EAS) AF: 0.382 AC: 15167 AN: 39700

South Asian (SAS) AF: 0.630 AC: 54375 AN: 86256

European-Finnish (FIN) AF: 0.754 AC: 40265 AN: 53390

Middle Eastern (MID) AF: 0.627 AC: 3618 AN: 5768

European-Non Finnish (NFE) AF: 0.794 AC: 882422 AN: 1112010

Other (OTH) AF: 0.728 AC: 43969 AN: 60396

GnomAD4 genome AF: 0.693 AC: 104876 AN: 151438 Hom.: 37317 Cov.: 27 AF XY: 0.685 AC XY: 50617 AN XY: 73936

African (AFR) AF: 0.567 AC: 23368 AN: 41226

American (AMR) AF: 0.648 AC: 9855 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 2603 AN: 3462

East Asian (EAS) AF: 0.381 AC: 1939 AN: 5084

South Asian (SAS) AF: 0.612 AC: 2925 AN: 4776

European-Finnish (FIN) AF: 0.742 AC: 7768 AN: 10472

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.796 AC: 54056 AN: 67918

Other (OTH) AF: 0.694 AC: 1455 AN: 2098

Alfa AF: 0.750 Hom.: 142439

Bravo AF: 0.676

TwinsUK AF: 0.804 AC: 2981

ALSPAC AF: 0.791 AC: 3048

ESP6500AA AF: 0.574 AC: 2529

ESP6500EA AF: 0.789 AC: 6787

ExAC AF: 0.690 AC: 83758

Asia WGS AF: 0.545 AC: 1901 AN: 3478

EpiCase AF: 0.789

EpiControl AF: 0.782

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Freeman-Sheldon syndrome (2)
-	-	1	Arthrogryposis, distal, type 2B3 (1)
-	-	1	Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A (1)
-	-	1	Contractures, pterygia, and variable skeletal fusions syndrome 1B (1)
-	-	1	Distal arthrogryposis type 2B1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.2
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0000083	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.95	L
PhyloP100		-0.76
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.52	T
Polyphen		0.014	B
Vest4		0.0080
MPC		0.25
ClinPred		0.0016	T
GERP RS		-2.1
Varity_R		0.027
gMVP		0.15
Mutation Taster		=98/2	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: rs2285477; hg19: chr17-10541515; COSMIC: COSV56862237;