22-40411425-G-A

Variant names:

• chr22-40411425-G-A
• rs2052532172
• NM_020831.6:c.3061C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020831.6(MRTFA):​c.3061C>T​(p.His1021Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H1021H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRTFA NM_020831.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.42
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.350289).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRTFA	NM_020831.6	c.3061C>T	p.His1021Tyr	missense_variant	Exon 15 of 15	ENST00000355630.10	NP_065882.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRTFA	ENST00000355630.10	c.3061C>T	p.His1021Tyr	missense_variant	Exon 15 of 15	1	NM_020831.6	ENSP00000347847.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000211 AC: 3 AN: 1422728 Hom.: 0 Cov.: 31 AF XY: 0.00000285 AC XY: 2 AN XY: 700922

African (AFR) AF: 0.00 AC: 0 AN: 32800

American (AMR) AF: 0.00 AC: 0 AN: 42488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24284

East Asian (EAS) AF: 0.00 AC: 0 AN: 38876

South Asian (SAS) AF: 0.00 AC: 0 AN: 82740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1084914

Other (OTH) AF: 0.00 AC: 0 AN: 58522

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 31, 2024

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 921 of the MKL1 protein (p.His921Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MKL1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.14
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T;T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.35	T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
PhyloP100		6.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D;.;D;D;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.014	D;.;D;D;.;.
Sift4G	Uncertain	0.039	D;D;D;D;T;D
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.55
MutPred		0.47		Loss of disorder (P = 0.031);.;.;Loss of disorder (P = 0.031);.;.;
MVP		0.15
MPC		0.30
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.29
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs2052532172; hg19: chr22-40807429;