rs35230241

Positions:

• chr17-10635772-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_002470.4(MYH3):​c.3938C>T​(p.Thr1313Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,614,128 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (96 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (79 hom.)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.19

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH3. . Gene score misZ 1.7445 (greater than the threshold 3.09). Trascript score misZ 4.649 (greater than threshold 3.09). GenCC has associacion of gene with spondylocarpotarsal synostosis syndrome, contractures, pterygia, and variable skeletal fusions syndrome 1B, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, digitotalar dysmorphism, autosomal recessive multiple pterygium syndrome, Freeman-Sheldon syndrome, distal arthrogryposis type 2B1, Sheldon-hall syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023226738).
• BP6: Variant 17-10635772-G-A is Benign according to our data. Variant chr17-10635772-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10635772-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.3938C>T	p.Thr1313Ile	missense_variant	29/41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.3938C>T	p.Thr1313Ile	missense_variant	29/41		XP_011522172.1
MYH3	XM_011523871.3	c.3938C>T	p.Thr1313Ile	missense_variant	29/41		XP_011522173.1
MYH3	XM_047436127.1	c.3938C>T	p.Thr1313Ile	missense_variant	31/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.3938C>T	p.Thr1313Ile	missense_variant	29/41	5	NM_002470.4	ENSP00000464317	P1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3025 AN: 152134 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.0681

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00590 AC: 1485 AN: 251492 Hom.: 40 AF XY: 0.00420 AC XY: 571 AN XY: 135922

Gnomad AFR exome AF: 0.0728

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00223 AC: 3255 AN: 1461876 Hom.: 79 Cov.: 32 AF XY: 0.00191 AC XY: 1386 AN XY: 727246

Gnomad4 AFR exome AF: 0.0695

Gnomad4 AMR exome AF: 0.00633

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.000730

Gnomad4 SAS exome AF: 0.000556

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.00517

GnomAD4 genome AF: 0.0199 AC: 3032 AN: 152252 Hom.: 96 Cov.: 33 AF XY: 0.0186 AC XY: 1387 AN XY: 74464

Gnomad4 AFR AF: 0.0679

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00452 Hom.: 29

Bravo AF: 0.0221

ESP6500AA AF: 0.0744 AC: 328

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00713 AC: 866

Asia WGS AF: 0.0220 AC: 75 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 27, 2015	- -

Freeman-Sheldon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Distal arthrogryposis type 2B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.19
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.47
MPC		0.27
ClinPred		0.0067	T
GERP RS		2.9
Varity_R		0.036
gMVP		0.052

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

Publications

LitVar

Other links and lift over

dbSNP: rs35230241; hg19: chr17-10539089;