Genetic Variant NM_013293.5:c.812G>T (chr7-23505772-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_013293.5(TRA2A):c.812G>T(p.Arg271Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,409,120 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TRA2A
NM_013293.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.29

Publications

0 publications found

Variant links:

Genes affected

TRA2A (HGNC:16645): (transformer 2 alpha homolog) This gene is a member of the transformer 2 homolog family and encodes a protein with several RRM (RNA recognition motif) domains. This phosphorylated nuclear protein binds to specific RNA sequences and plays a role in the regulation of pre-mRNA splicing. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

TRA2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013293.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRA2A	NM_013293.5	MANE Select	c.812G>T	p.Arg271Leu	missense	Exon 7 of 8	NP_037425.1	Q13595-1
TRA2A	NM_001362759.2		c.623G>T	p.Arg208Leu	missense	Exon 6 of 7	NP_001349688.1
TRA2A	NM_001282757.2		c.509G>T	p.Arg170Leu	missense	Exon 8 of 9	NP_001269686.1	Q13595-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRA2A	ENST00000297071.9	TSL:1 MANE Select	c.812G>T	p.Arg271Leu	missense	Exon 7 of 8	ENSP00000297071.4	Q13595-1
TRA2A	ENST00000870823.1		c.809G>T	p.Arg270Leu	missense	Exon 7 of 8	ENSP00000540882.1
TRA2A	ENST00000870824.1		c.743G>T	p.Arg248Leu	missense	Exon 7 of 8	ENSP00000540883.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1409120

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

700708

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30632

American (AMR)

AF:

0.00

AC:

AN:

31850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24054

East Asian (EAS)

AF:

0.00

AC:

AN:

38366

South Asian (SAS)

AF:

0.0000392

AC:

AN:

76534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5454

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092100

Other (OTH)

AF:

0.00

AC:

AN:

57798

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00250614), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.22

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

3.1

PhyloP100

7.3

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.4

REVEL

Uncertain

0.38

Sift

Benign

0.20

Sift4G

Benign

0.12

Polyphen

0.96

Vest4

0.73

MutPred

0.25

Loss of methylation at R271 (P = 0.0167)

MVP

0.37

MPC

1.5

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.66

Mutation Taster

=50/50

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over