1-231953994-A-G

Variant names:

• chr1-231953994-A-G
• rs9431736
• NM_018662.3:c.1982-4834A>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.1982-4834A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 152,134 control chromosomes in the GnomAD database, including 1,869 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 0.15 (1869 hom., cov: 32)
• Consequence: DISC1 NM_018662.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.331 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.1982-4834A>G		intron	N/A	NP_061132.2
	DISC1	NM_001164537.2		c.2078-4834A>G		intron	N/A	NP_001158009.1
	DISC1	NM_001012957.2		c.1982-4834A>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.1982-4834A>G		intron	N/A	ENSP00000403888.4
	DISC1	ENST00000366637.8	TSL:5	c.1982-4834A>G		intron	N/A	ENSP00000355597.6
	DISC1	ENST00000535983.5	TSL:1	c.1982-54791A>G		intron	N/A	ENSP00000443996.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22503 AN: 152016 Hom.: 1866 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.142

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

GnomAD4 genome AF: 0.148 AC: 22531 AN: 152134 Hom.: 1869 Cov.: 32 AF XY: 0.152 AC XY: 11269 AN XY: 74368

African (AFR) AF: 0.171 AC: 7113 AN: 41490

American (AMR) AF: 0.165 AC: 2516 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3470

East Asian (EAS) AF: 0.345 AC: 1778 AN: 5158

South Asian (SAS) AF: 0.231 AC: 1112 AN: 4810

European-Finnish (FIN) AF: 0.118 AC: 1247 AN: 10602

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.116 AC: 7881 AN: 68000

Other (OTH) AF: 0.144 AC: 305 AN: 2112

Alfa AF: 0.136 Hom.: 2780

Bravo AF: 0.152

Asia WGS AF: 0.272 AC: 943 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.66
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: rs9431736; hg19: chr1-232089740;