22-40424147-T-C

Variant names:

• chr22-40424147-T-C
• rs5757949
• NM_020831.6:c.777+59A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020831.6(MRTFA):​c.777+59A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,486,938 control chromosomes in the GnomAD database, including 63,515 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (5060 hom., cov: 32)
  • Exomes 𝑓: 0.29 (58455 hom.)
• Consequence: MRTFA NM_020831.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.182
• Publications: 20 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.341 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRTFA	NM_020831.6	MANE Select	c.777+59A>G		intron	N/A	NP_065882.2
	MRTFA	NM_001282661.3		c.777+59A>G		intron	N/A	NP_001269590.2
	MRTFA	NM_001318139.2		c.582+59A>G		intron	N/A	NP_001305068.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRTFA	ENST00000355630.10	TSL:1 MANE Select	c.777+59A>G		intron	N/A	ENSP00000347847.5
	MRTFA	ENST00000402042.7	TSL:1	c.777+59A>G		intron	N/A	ENSP00000385584.3
	MRTFA	ENST00000407029.7	TSL:1	c.477+59A>G		intron	N/A	ENSP00000385835.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34969 AN: 151958 Hom.: 5062 Cov.: 32

Gnomad AFR AF: 0.0593

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.271

GnomAD4 exome AF: 0.290 AC: 386900 AN: 1334862 Hom.: 58455 AF XY: 0.288 AC XY: 188897 AN XY: 656114

African (AFR) AF: 0.0470 AC: 1322 AN: 28100

American (AMR) AF: 0.177 AC: 4417 AN: 24934

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 7208 AN: 20454

East Asian (EAS) AF: 0.334 AC: 11612 AN: 34722

South Asian (SAS) AF: 0.176 AC: 11694 AN: 66604

European-Finnish (FIN) AF: 0.316 AC: 15557 AN: 49164

Middle Eastern (MID) AF: 0.324 AC: 1234 AN: 3810

European-Non Finnish (NFE) AF: 0.302 AC: 318066 AN: 1052090

Other (OTH) AF: 0.287 AC: 15790 AN: 54984

GnomAD4 genome AF: 0.230 AC: 34951 AN: 152076 Hom.: 5060 Cov.: 32 AF XY: 0.228 AC XY: 16953 AN XY: 74354

African (AFR) AF: 0.0591 AC: 2453 AN: 41502

American (AMR) AF: 0.220 AC: 3357 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1295 AN: 3472

East Asian (EAS) AF: 0.354 AC: 1830 AN: 5168

South Asian (SAS) AF: 0.178 AC: 859 AN: 4826

European-Finnish (FIN) AF: 0.314 AC: 3318 AN: 10572

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20888 AN: 67928

Other (OTH) AF: 0.269 AC: 569 AN: 2112

Alfa AF: 0.295 Hom.: 17446

Bravo AF: 0.218

Asia WGS AF: 0.217 AC: 752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.69
PhyloP100		0.18
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: rs5757949; hg19: chr22-40820151; COSMIC: COSV62934863;