22-40418496-T-C

Position:

• chr22-40418496-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000355630.10(MRTFA):​c.2242A>G​(p.Ser748Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,607,588 control chromosomes in the GnomAD database, including 145,842 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S748R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.50 (23605 hom., cov: 32)
  • Exomes 𝑓: 0.40 (122237 hom.)
• Consequence: MRTFA ENST00000355630.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.06

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1725998E-6).
• BP6: Variant 22-40418496-T-C is Benign according to our data. Variant chr22-40418496-T-C is described in ClinVar as [Benign]. Clinvar id is 1170078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRTFA	NM_020831.6	c.2242A>G	p.Ser748Gly	missense_variant	12/15	ENST00000355630.10	NP_065882.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRTFA	ENST00000355630.10	c.2242A>G	p.Ser748Gly	missense_variant	12/15	1	NM_020831.6	ENSP00000347847

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76609 AN: 151846 Hom.: 23537 Cov.: 32

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.454

GnomAD3 exomes AF: 0.384 AC: 93123 AN: 242442 Hom.: 21434 AF XY: 0.387 AC XY: 50973 AN XY: 131676

Gnomad AFR exome AF: 0.879

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.413

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.471

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.398 AC: 578924 AN: 1455622 Hom.: 122237 Cov.: 51 AF XY: 0.399 AC XY: 288978 AN XY: 724332

Gnomad4 AFR exome AF: 0.891

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.329

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.505 AC: 76730 AN: 151966 Hom.: 23605 Cov.: 32 AF XY: 0.495 AC XY: 36727 AN XY: 74254

Gnomad4 AFR AF: 0.867

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.463

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.393

Gnomad4 OTH AF: 0.457

Alfa AF: 0.404 Hom.: 24055

Bravo AF: 0.513

TwinsUK AF: 0.371 AC: 1376

ALSPAC AF: 0.383 AC: 1475

ESP6500AA AF: 0.861 AC: 3792

ESP6500EA AF: 0.397 AC: 3414

ExAC AF: 0.396 AC: 48095

Asia WGS AF: 0.363 AC: 1263 AN: 3476

EpiCase AF: 0.409

EpiControl AF: 0.405

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0050
DANN	Benign	0.44
DEOGEN2	Benign	0.034	T;.;T;T;T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.041	.;T;T;T;T;T;T
MetaRNN	Benign	0.0000012	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.26	N;.;.;N;N;N;.
REVEL	Benign	0.077
Sift	Benign	0.41	T;.;.;T;T;T;.
Sift4G	Benign	0.51	T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;B;B;.
Vest4		0.040
MPC		0.045
ClinPred		0.0086	T
GERP RS		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034

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

Other links and lift over

dbSNP: rs878756; hg19: chr22-40814500; COSMIC: COSV62931934; COSMIC: COSV62931934;