rs2273890

Variant names:

• chr1-231795302-T-C
• rs2273890
• NM_018662.3:c.1689+6T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_018662.3(DISC1):​c.1689+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,609,354 control chromosomes in the GnomAD database, including 13,975 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1218 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12757 hom.)
• Consequence: DISC1 NM_018662.3 splice_region, intron
• Scores: Splicing: ADA: 0.1883
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50
• Publications: 11 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]

ENSG00000286071 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3	c.1689+6T>C		splice_region_variant, intron_variant	Intron 7 of 12	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.1689+6T>C		splice_region_variant, intron_variant	Intron 7 of 12	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.1689+6T>C		splice_region_variant, intron_variant	Intron 7 of 12	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.*1550+6T>C		splice_region_variant, intron_variant	Intron 11 of 12	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18548 AN: 152092 Hom.: 1214 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.0887

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0671

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.115 AC: 28597 AN: 247988 AF XY: 0.115

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0791

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.118

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.130 AC: 188813 AN: 1457146 Hom.: 12757 Cov.: 30 AF XY: 0.128 AC XY: 92653 AN XY: 725198

African (AFR) AF: 0.112 AC: 3729 AN: 33396

American (AMR) AF: 0.0797 AC: 3563 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3026 AN: 26098

East Asian (EAS) AF: 0.116 AC: 4581 AN: 39652

South Asian (SAS) AF: 0.0674 AC: 5810 AN: 86162

European-Finnish (FIN) AF: 0.123 AC: 6559 AN: 53130

Middle Eastern (MID) AF: 0.114 AC: 655 AN: 5766

European-Non Finnish (NFE) AF: 0.139 AC: 153639 AN: 1108028

Other (OTH) AF: 0.120 AC: 7251 AN: 60234

GnomAD4 genome AF: 0.122 AC: 18570 AN: 152208 Hom.: 1218 Cov.: 32 AF XY: 0.119 AC XY: 8883 AN XY: 74398

African (AFR) AF: 0.111 AC: 4620 AN: 41552

American (AMR) AF: 0.0888 AC: 1357 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3468

East Asian (EAS) AF: 0.117 AC: 607 AN: 5168

South Asian (SAS) AF: 0.0667 AC: 322 AN: 4826

European-Finnish (FIN) AF: 0.124 AC: 1316 AN: 10594

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9390 AN: 67994

Other (OTH) AF: 0.117 AC: 248 AN: 2112

Alfa AF: 0.129 Hom.: 1067

Bravo AF: 0.122

Asia WGS AF: 0.0800 AC: 278 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.129

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		1.5
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.19
dbscSNV1_RF	Benign	0.29
SpliceAI score (max)		0.090		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: rs2273890; hg19: chr1-231931048; COSMIC: COSV54408055;