22-40411410-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020831.6(MRTFA):c.3076C>T(p.His1026Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000083 in 1,566,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1026Q) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

MRTFA
NM_020831.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94

Publications

0 publications found

Variant links:

Genes affected

MRTFA (HGNC:14334): (myocardin related transcription factor A) The protein encoded by this gene interacts with the transcription factor myocardin, a key regulator of smooth muscle cell differentiation. The encoded protein is predominantly nuclear and may help transduce signals from the cytoskeleton to the nucleus. This gene is involved in a specific translocation event that creates a fusion of this gene and the RNA-binding motif protein-15 gene. This translocation has been associated with acute megakaryocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

MRTFA Gene-Disease associations (from GenCC):

immunodeficiency 66
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

MRTFA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRTFA	NM_020831.6 link	c.3076C>T	p.His1026Tyr	missense_variant	Exon 15 of 15	ENST00000355630.10	NP_065882.2	Q969V6A4FUJ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRTFA	ENST00000355630.10 link	c.3076C>T	p.His1026Tyr	missense_variant	Exon 15 of 15	1	NM_020831.6	ENSP00000347847.5		A0A499FIJ6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000438

AC:

AN:

228188

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000778

AC:

AN:

1413876

Hom.:

Cov.:

AF XY:

0.00000719

AC XY:

AN XY:

695206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32714

American (AMR)

AF:

0.00

AC:

AN:

42262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23520

East Asian (EAS)

AF:

0.00

AC:

AN:

38838

South Asian (SAS)

AF:

0.00

AC:

AN:

80640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.0000102

AC:

AN:

1080058

Other (OTH)

AF:

0.00

AC:

AN:

58172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74370

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 30, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 926 of the MKL1 protein (p.His926Tyr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MKL1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;T;T;D;T;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

.;D;D;D;D;D

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.63

D;D;D;D;D;D

MetaSVM

Benign

-0.59

PhyloP100

8.9

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.6

D;.;D;D;.;.

REVEL

Uncertain

0.38

Sift

Benign

0.038

D;.;T;D;.;.

Sift4G

Uncertain

0.024

D;D;D;D;D;D

Polyphen

0.99

D;.;D;D;.;.

Vest4

0.67

MutPred

0.52

Loss of disorder (P = 0.0219);.;.;Loss of disorder (P = 0.0219);.;.;

MVP

0.50

MPC

0.30

ClinPred

0.99

GERP RS

4.8

Varity_R

0.60

Mutation Taster

=59/41

polymorphism

(source)

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

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22-40411410-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over