1-232009141-A-G

Variant names:

• chr1-232009141-A-G
• rs821617
• ENST00000535983.5:c.*250A>G

Variant summary

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

The NM_001164538.2(DISC1):​c.2399A>G​(p.Lys800Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,575,808 control chromosomes in the GnomAD database, including 62,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (6466 hom., cov: 31)
  • Exomes 𝑓: 0.28 (56278 hom.)
• Consequence: DISC1 NM_001164538.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.351
• Publications: 17 publications found

Genes affected

DISC1 (HGNC:2888): (DISC1 scaffold protein) This gene encodes a protein with multiple coiled coil motifs which is located in the nucleus, cytoplasm and mitochondria. The protein is involved in neurite outgrowth and cortical development through its interaction with other proteins. This gene is disrupted in a t(1;11)(q42.1;q14.3) translocation which segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.015).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164538.2. 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
	DISC1	NM_018662.3	MANE Select	c.2307+92A>G		intron	N/A	NP_061132.2	Q9NRI5-1
	DISC1	NM_001164538.2		c.2399A>G	p.Lys800Arg	missense	Exon 11 of 11	NP_001158010.1	C4P098
	DISC1	NM_001164541.2		c.*250A>G		3_prime_UTR	Exon 10 of 10	NP_001158013.1	Q9NRI5-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	ENST00000535983.5	TSL:1	c.*250A>G		3_prime_UTR	Exon 10 of 10	ENSP00000443996.1	Q9NRI5-8
	DISC1	ENST00000439617.8	TSL:5 MANE Select	c.2307+92A>G		intron	N/A	ENSP00000403888.4	Q9NRI5-1
	DISC1	ENST00000366637.8	TSL:5	c.2241+158A>G		intron	N/A	ENSP00000355597.6	Q9NRI5-2

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43312 AN: 151778 Hom.: 6460 Cov.: 31

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.259 AC: 52882 AN: 204542 AF XY: 0.263

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.277 AC: 394268 AN: 1423912 Hom.: 56278 Cov.: 31 AF XY: 0.278 AC XY: 195492 AN XY: 703868

African (AFR) AF: 0.341 AC: 11198 AN: 32816

American (AMR) AF: 0.129 AC: 5171 AN: 39974

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 5966 AN: 25260

East Asian (EAS) AF: 0.114 AC: 4418 AN: 38828

South Asian (SAS) AF: 0.274 AC: 22127 AN: 80716

European-Finnish (FIN) AF: 0.322 AC: 16621 AN: 51680

Middle Eastern (MID) AF: 0.264 AC: 1463 AN: 5532

European-Non Finnish (NFE) AF: 0.286 AC: 311629 AN: 1090246

Other (OTH) AF: 0.266 AC: 15675 AN: 58860

GnomAD4 genome AF: 0.285 AC: 43346 AN: 151896 Hom.: 6466 Cov.: 31 AF XY: 0.284 AC XY: 21106 AN XY: 74206

African (AFR) AF: 0.332 AC: 13771 AN: 41436

American (AMR) AF: 0.179 AC: 2737 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 842 AN: 3464

East Asian (EAS) AF: 0.121 AC: 622 AN: 5160

South Asian (SAS) AF: 0.274 AC: 1315 AN: 4800

European-Finnish (FIN) AF: 0.331 AC: 3483 AN: 10536

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19560 AN: 67940

Other (OTH) AF: 0.256 AC: 539 AN: 2106

Alfa AF: 0.273 Hom.: 6013

Bravo AF: 0.272

Asia WGS AF: 0.216 AC: 752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.6
DANN	Benign	0.52
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs821617; hg19: chr1-232144887; COSMIC: COSV64110667; COSMIC: COSV64110667;