chr17-10418769-G-T

Position:

chr17-10418769-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2

The NM_002472.3(MYH8):c.387C>A(p.Asn129Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,772 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

MYH8
NM_002472.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.40

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 Uncertain_significance. 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, 0.975

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH8	NM_002472.3 linkuse as main transcript	c.387C>A	p.Asn129Lys	missense_variant	5/40	ENST00000403437.2	NP_002463.2	P13535
MYHAS	NR_125367.1 linkuse as main transcript	n.167+12531G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYH8	ENST00000403437.2 linkuse as main transcript	c.387C>A	p.Asn129Lys	missense_variant	5/40	5	NM_002472.3	ENSP00000384330.2	P13535
ENSG00000272736	ENST00000399342.6 linkuse as main transcript	n.206+12492G>T		intron_variant		3
ENSG00000272736	ENST00000581304.1 linkuse as main transcript	n.143+12531G>T		intron_variant		3
MYHAS	ENST00000587182.2 linkuse as main transcript	n.155+12531G>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000320

AC:

AN:

250204

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

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

AF:

0.00000684

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.387C>A (p.N129K) alteration is located in exon 5 (coding exon 3) of the MYH8 gene. This alteration results from a C to A substitution at nucleotide position 387, causing the asparagine (N) at amino acid position 129 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.011

Polyphen

0.98

Vest4

0.90

MutPred

0.92

Gain of methylation at N129 (P = 0.0102);

MVP

0.94

MPC

2.5

ClinPred

0.99

GERP RS

2.8

Varity_R

0.92

gMVP

0.84

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over