7-23506228-C-T

Variant names:

• chr7-23506228-C-T
• rs371167724
• NM_013293.5:c.680G>A

Variant summary

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

The NM_013293.5(TRA2A):​c.680G>A​(p.Gly227Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,266 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. G227V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRA2A NM_013293.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.06
• Publications: 0 publications found

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]

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRA2A	NM_013293.5	MANE Select	c.680G>A	p.Gly227Asp	missense	Exon 6 of 8	NP_037425.1	Q13595-1
	TRA2A	NM_001362759.2		c.491G>A	p.Gly164Asp	missense	Exon 5 of 7	NP_001349688.1
	TRA2A	NM_001282757.2		c.377G>A	p.Gly126Asp	missense	Exon 7 of 9	NP_001269686.1	Q13595-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRA2A	ENST00000297071.9	TSL:1 MANE Select	c.680G>A	p.Gly227Asp	missense	Exon 6 of 8	ENSP00000297071.4	Q13595-1
	TRA2A	ENST00000870823.1		c.677G>A	p.Gly226Asp	missense	Exon 6 of 8	ENSP00000540882.1
	TRA2A	ENST00000870824.1		c.611G>A	p.Gly204Asp	missense	Exon 6 of 8	ENSP00000540883.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250312 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460266 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726512

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

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110848

Other (OTH) AF: 0.00 AC: 0 AN: 60280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	23
DANN	Benign	0.38
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.29
Sift	Benign	0.31	T
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.72
MutPred		0.32		Loss of MoRF binding (P = 0.0594)
MVP		0.78
MPC		1.6
ClinPred		0.46	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.56
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs371167724; hg19: chr7-23545847;