17-10420067-A-G

Position:

chr17-10420067-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2

The NM_002472.3(MYH8):c.161T>C(p.Ile54Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,614,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

MYH8
NM_002472.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.10

Variant links:

Genes affected

MYH8 (HGNC:7578): (myosin heavy chain 8) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is predominantly expressed in fetal skeletal muscle. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in trismus-pseudocamptodactyly syndrome. [provided by RefSeq, Sep 2009]

MYH8 links:

ENSG00000272736 (HGNC:):

ENSG00000272736 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH8. . Gene score misZ 0.34953 (greater than the threshold 3.09). Trascript score misZ 3.2125 (greater than threshold 3.09). GenCC has associacion of gene with trismus-pseudocamptodactyly syndrome, Carney complex - trismus - pseudocamptodactyly syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH8	NM_002472.3 linkuse as main transcript	c.161T>C	p.Ile54Thr	missense_variant	3/40	ENST00000403437.2	NP_002463.2	P13535
MYHAS	NR_125367.1 linkuse as main transcript	n.167+13829A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYH8	ENST00000403437.2 linkuse as main transcript	c.161T>C	p.Ile54Thr	missense_variant	3/40	5	NM_002472.3	ENSP00000384330.2	P13535
ENSG00000272736	ENST00000399342.6 linkuse as main transcript	n.206+13790A>G		intron_variant		3
ENSG00000272736	ENST00000581304.1 linkuse as main transcript	n.143+13829A>G		intron_variant		3
MYHAS	ENST00000587182.2 linkuse as main transcript	n.155+13829A>G		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152204

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:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251128

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000766

AC:

112

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.0000737

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000481

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 17, 2022	The c.161T>C (p.I54T) alteration is located in exon 3 (coding exon 1) of the MYH8 gene. This alteration results from a T to C substitution at nucleotide position 161, causing the isoleucine (I) at amino acid position 54 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 05, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

0.0023

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.3

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.22

Vest4

0.75

MVP

0.94

MPC

0.58

ClinPred

0.74

GERP RS

4.6

Varity_R

0.55

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over