1-231564697-G-T

Variant names:

• chr1-231564697-G-T
• rs762657262
• NM_005999.3:c.665G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005999.3(TSNAX):​c.665G>T​(p.Arg222Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R222H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSNAX NM_005999.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.41
• Publications: 0 publications found

Genes affected

TSNAX (HGNC:12380): (translin associated factor X) This gene encodes a protein which specifically interacts with translin, a DNA-binding protein that binds consensus sequences at breakpoint junctions of chromosomal translocations. The encoded protein contains bipartite nuclear targeting sequences that may provide nuclear transport for translin, which lacks any nuclear targeting motifs. [provided by RefSeq, Jul 2008]

TSNAX-DISC1 (HGNC:49177): (TSNAX-DISC1 readthrough (NMD candidate)) This gene represents naturally occurring read-through transcription between the neighboring TSNAX (translin-associated factor X) and DISC1 (disrupted in schizophrenia 1) genes on chromosome 1. Alternative splicing results in multiple transcript variants, all of which are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to be protein-coding. These alterations in gene processing may be associated with risk for psychiatric illness, most notably, schizophrenia. [provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005999.3. 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
	TSNAX	NM_005999.3	MANE Select	c.665G>T	p.Arg222Leu	missense	Exon 6 of 6	NP_005990.1	Q99598
	TSNAX-DISC1	NR_028393.1		n.525+22086G>T		intron	N/A
	TSNAX-DISC1	NR_028394.1		n.653+3442G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSNAX	ENST00000366639.9	TSL:1 MANE Select	c.665G>T	p.Arg222Leu	missense	Exon 6 of 6	ENSP00000355599.3	Q99598
	TSNAX-DISC1	ENST00000602956.5	TSL:2	n.495+3442G>T		intron	N/A	ENSP00000473532.1	C4P0D8
	TSNAX	ENST00000947977.1		c.710G>T	p.Arg237Leu	missense	Exon 6 of 6	ENSP00000618036.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.55		Loss of helix (P = 0.028)
MVP		0.37
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.89
Mutation Taster		=17/83	disease causing

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: rs762657262; hg19: chr1-231700443; COSMIC: COSV64147189; COSMIC: COSV64147189;