chr1-232001928-T-C

Variant names:

• chr1-232001928-T-C
• rs1754605
• NM_018662.3:c.2043-6857T>C

Variant summary

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

The NM_001164537.2(DISC1):​c.2139-6857T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,018 control chromosomes in the GnomAD database, including 6,582 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 0.29 (6582 hom., cov: 32)
• Consequence: DISC1 NM_001164537.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164537.2. 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.2043-6857T>C		intron	N/A	NP_061132.2
	DISC1	NM_001164537.2		c.2139-6857T>C		intron	N/A	NP_001158009.1
	DISC1	NM_001012957.2		c.2043-6857T>C		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.2043-6857T>C		intron	N/A	ENSP00000403888.4
	DISC1	ENST00000366637.8	TSL:5	c.2043-6857T>C		intron	N/A	ENSP00000355597.6
	DISC1	ENST00000535983.5	TSL:1	c.1982-6857T>C		intron	N/A	ENSP00000443996.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43775 AN: 151900 Hom.: 6575 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.258

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

GnomAD4 genome AF: 0.288 AC: 43815 AN: 152018 Hom.: 6582 Cov.: 32 AF XY: 0.287 AC XY: 21300 AN XY: 74304

African (AFR) AF: 0.341 AC: 14129 AN: 41454

American (AMR) AF: 0.183 AC: 2791 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3472

East Asian (EAS) AF: 0.120 AC: 619 AN: 5178

South Asian (SAS) AF: 0.274 AC: 1321 AN: 4818

European-Finnish (FIN) AF: 0.330 AC: 3471 AN: 10534

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

European-Non Finnish (NFE) AF: 0.288 AC: 19599 AN: 67962

Other (OTH) AF: 0.261 AC: 552 AN: 2112

Alfa AF: 0.277 Hom.: 1018

Bravo AF: 0.276

Asia WGS AF: 0.220 AC: 763 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.37
DANN	Benign	0.65
PhyloP100		-1.9
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: rs1754605; hg19: chr1-232137674; COSMIC: COSV64093781;