22-40411488-G-T

Variant names:

• chr22-40411488-G-T
• NM_020831.6:c.2998C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020831.6(MRTFA):​c.2998C>A​(p.Leu1000Met) 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRTFA NM_020831.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11346921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRTFA	NM_020831.6	c.2998C>A	p.Leu1000Met	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.2998C>A	p.Leu1000Met	missense_variant	Exon 15 of 15	1	NM_020831.6	ENSP00000347847.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. This variant has not been reported in the literature in individuals affected with MKL1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 900 of the MKL1 protein (p.Leu900Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.045	T;T;T;T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	.;T;T;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.39	N;.;N;N;.;.
REVEL	Benign	0.058
Sift	Benign	0.093	T;.;T;T;.;.
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.14	B;.;B;B;.;.
Vest4		0.16
MutPred		0.43		Gain of catalytic residue at L900 (P = 0.0474);.;.;Gain of catalytic residue at L900 (P = 0.0474);.;.;
MVP		0.27
MPC		0.32
ClinPred		0.71	D
GERP RS		4.8
Varity_R		0.069

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-40807492;