Variant chr17-10445085-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_017533.2(MYH4):c.5357T>C(p.Met1786Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,518 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYH4
NM_017533.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.23

Variant links:

Genes affected

MYH4 (HGNC:7574): (myosin heavy chain 4) Enables double-stranded RNA binding activity. Involved in muscle contraction. Located in myofibril. [provided by Alliance of Genome Resources, Apr 2022]

MYH4 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYH4	NM_017533.2 linkuse as main transcript	c.5357T>C	p.Met1786Thr	missense_variant	37/40	ENST00000255381.2
MYHAS	NR_125367.1 linkuse as main transcript	n.167+38847A>G		intron_variant, non_coding_transcript_variant
MYH4	XM_017024676.2 linkuse as main transcript	c.5357T>C	p.Met1786Thr	missense_variant	35/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MYH4	ENST00000255381.2 linkuse as main transcript	c.5357T>C	p.Met1786Thr	missense_variant	37/40	1	NM_017533.2	P1
	ENST00000399342.6 linkuse as main transcript	n.206+38808A>G		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1 linkuse as main transcript	n.143+38847A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151662

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74068

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

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

Feb 28, 2024

The c.5357T>C (p.M1786T) alteration is located in exon 37 (coding exon 35) of the MYH4 gene. This alteration results from a T to C substitution at nucleotide position 5357, causing the methionine (M) at amino acid position 1786 to be replaced by a threonine (T). 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

0.63

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.71

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.25

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.80

Sift

Benign

0.054

Sift4G

Benign

0.13

Polyphen

0.86

Vest4

0.89

MVP

0.93

MPC

0.75

ClinPred

1.0

GERP RS

5.5

Varity_R

0.27

gMVP

0.21

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