1-231991141-A-G

Variant names:

• chr1-231991141-A-G
• rs821653
• NM_018662.3:c.2043-17644A>G

Variant summary

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

The NM_018662.3(DISC1):​c.2043-17644A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 152,172 control chromosomes in the GnomAD database, including 5,893 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 0.27 (5893 hom., cov: 33)
• Consequence: DISC1 NM_018662.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 4 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 (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018662.3. 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
	DISC1	NM_018662.3	MANE Select	c.2043-17644A>G		intron	N/A	NP_061132.2
	DISC1	NM_001164537.2		c.2139-17644A>G		intron	N/A	NP_001158009.1
	DISC1	NM_001012957.2		c.2043-17644A>G		intron	N/A	NP_001012975.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	ENST00000439617.8	TSL:5 MANE Select	c.2043-17644A>G		intron	N/A	ENSP00000403888.4
	DISC1	ENST00000366637.8	TSL:5	c.2043-17644A>G		intron	N/A	ENSP00000355597.6
	DISC1	ENST00000535983.5	TSL:1	c.1982-17644A>G		intron	N/A	ENSP00000443996.1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41428 AN: 152054 Hom.: 5888 Cov.: 33

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.244

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.272 AC: 41466 AN: 152172 Hom.: 5893 Cov.: 33 AF XY: 0.272 AC XY: 20225 AN XY: 74382

African (AFR) AF: 0.289 AC: 11993 AN: 41496

American (AMR) AF: 0.175 AC: 2683 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3472

East Asian (EAS) AF: 0.120 AC: 621 AN: 5170

South Asian (SAS) AF: 0.276 AC: 1331 AN: 4820

European-Finnish (FIN) AF: 0.330 AC: 3502 AN: 10602

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

European-Non Finnish (NFE) AF: 0.287 AC: 19489 AN: 68000

Other (OTH) AF: 0.247 AC: 523 AN: 2116

Alfa AF: 0.281 Hom.: 1448

Bravo AF: 0.257

Asia WGS AF: 0.219 AC: 766 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.1
DANN	Benign	0.85
PhyloP100		1.1
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: rs821653; hg19: chr1-232126887; COSMIC: COSV64093703;