22-40418496-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020831.6(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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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. S748R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.50 (23605 hom., cov: 32)
  • Exomes 𝑓: 0.40 (122237 hom.)
• Consequence: MRTFA NM_020831.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020831.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRTFA	NM_020831.6	MANE Select	c.2242A>G	p.Ser748Gly	missense	Exon 12 of 15	NP_065882.2	A0A499FIJ6
	MRTFA	NM_001282661.3		c.2092A>G	p.Ser698Gly	missense	Exon 11 of 14	NP_001269590.2	B0QY83
	MRTFA	NM_001318139.2		c.2047A>G	p.Ser683Gly	missense	Exon 10 of 13	NP_001305068.1	W0Z7M9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRTFA	ENST00000355630.10	TSL:1 MANE Select	c.2242A>G	p.Ser748Gly	missense	Exon 12 of 15	ENSP00000347847.5	A0A499FIJ6
	MRTFA	ENST00000402042.7	TSL:1	c.2092A>G	p.Ser698Gly	missense	Exon 11 of 14	ENSP00000385584.3	B0QY83
	MRTFA	ENST00000407029.7	TSL:1	c.1942A>G	p.Ser648Gly	missense	Exon 9 of 12	ENSP00000385835.1	Q969V6

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

GnomAD2 exomes AF: 0.384 AC: 93123 AN: 242442 AF XY: 0.387

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 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

African (AFR) AF: 0.891 AC: 29688 AN: 33308

American (AMR) AF: 0.223 AC: 9460 AN: 42346

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10604 AN: 25640

East Asian (EAS) AF: 0.137 AC: 5421 AN: 39684

South Asian (SAS) AF: 0.468 AC: 40071 AN: 85666

European-Finnish (FIN) AF: 0.329 AC: 17536 AN: 53244

Middle Eastern (MID) AF: 0.486 AC: 2784 AN: 5730

European-Non Finnish (NFE) AF: 0.395 AC: 438608 AN: 1109894

Other (OTH) AF: 0.412 AC: 24752 AN: 60110

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

African (AFR) AF: 0.867 AC: 35957 AN: 41496

American (AMR) AF: 0.317 AC: 4843 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1425 AN: 3470

East Asian (EAS) AF: 0.118 AC: 603 AN: 5126

South Asian (SAS) AF: 0.463 AC: 2229 AN: 4810

European-Finnish (FIN) AF: 0.323 AC: 3420 AN: 10578

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26689 AN: 67884

Other (OTH) AF: 0.457 AC: 966 AN: 2114

Alfa AF: 0.427 Hom.: 41190

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.041	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.077
Sift	Benign	0.41	T
Sift4G	Benign	0.51	T
Polyphen		0.0	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
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV62931934; COSMIC: COSV62931934;