Variant 17-10628670-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_002470.4(MYH3):c.5806C>A(p.His1936Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

MYH3
NM_002470.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.96

Variant links:

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]

MYH3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. GenCC has associacion of the 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=0.28249687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4 link	c.5806C>A	p.His1936Asn	missense_variant	41/41	ENST00000583535.6	NP_002461.2	P11055Q5GJ67
MYH3	XM_011523870.4 link	c.5806C>A	p.His1936Asn	missense_variant	41/41		XP_011522172.1	P11055
MYH3	XM_011523871.3 link	c.5806C>A	p.His1936Asn	missense_variant	41/41		XP_011522173.1	P11055
MYH3	XM_047436127.1 link	c.5806C>A	p.His1936Asn	missense_variant	43/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYH3	ENST00000583535.6 link	c.5806C>A	p.His1936Asn	missense_variant	41/41	5	NM_002470.4	ENSP00000464317.1	P11055
MYH3	ENST00000577963.1 link	n.348C>A		non_coding_transcript_exon_variant	2/2	2
MYH3	ENST00000579928.2 link	n.336C>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249288

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134948

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

0.067

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.62

M_CAP

Benign

0.060

MetaRNN

Benign

0.28

MetaSVM

Uncertain

-0.0077

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.69

Sift4G

Benign

0.49

Polyphen

0.27

Vest4

0.49

MutPred

0.13

Gain of MoRF binding (P = 0.0964);

MVP

0.74

MPC

0.33

ClinPred

0.31

GERP RS

5.5

Varity_R

0.13

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over