22-40418496-T-G

Variant names:

• chr22-40418496-T-G
• rs878756
• NM_020831.6:c.2242A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020831.6(MRTFA):​c.2242A>C​(p.Ser748Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S748G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRTFA NM_020831.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.06
• Publications: 34 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07996124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRTFA	NM_020831.6	c.2242A>C	p.Ser748Arg	missense_variant	Exon 12 of 15	ENST00000355630.10	NP_065882.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRTFA	ENST00000355630.10	c.2242A>C	p.Ser748Arg	missense_variant	Exon 12 of 15	1	NM_020831.6	ENSP00000347847.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 41190

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.014
DANN	Benign	0.54
DEOGEN2	Benign	0.18	T;.;T;T;T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.45	.;T;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.080	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N;.;.;N;N;N;.
REVEL	Benign	0.034
Sift	Benign	0.13	T;.;.;T;T;T;.
Sift4G	Benign	0.29	T;T;T;T;T;T;T
Polyphen		0.17	B;.;.;B;B;B;.
Vest4		0.20
MutPred		0.21		Loss of ubiquitination at K651 (P = 0.0347);.;.;Loss of ubiquitination at K651 (P = 0.0347);.;Loss of ubiquitination at K651 (P = 0.0347);.;
MVP		0.24
MPC		0.079
ClinPred		0.098	T
GERP RS		-8.5
Varity_R		0.11
Mutation Taster		=99/1	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: rs878756; hg19: chr22-40814500;