rs4658954

Variant names:

• chr1-231843611-G-A
• rs4658954
• NM_018662.3:c.1981+25094G>A

Variant summary

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

The NM_018662.3(DISC1):​c.1981+25094G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 152,102 control chromosomes in the GnomAD database, including 32,833 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 0.65 (32833 hom., cov: 31)
• Consequence: DISC1 NM_018662.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.998
• Publications: 3 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]

ENSG00000286071 (HGNC:):

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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.759 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	NM_018662.3	MANE Select	c.1981+25094G>A		intron	N/A	NP_061132.2	Q9NRI5-1
	DISC1	NM_001164537.2		c.2077+25094G>A		intron	N/A	NP_001158009.1	C4P096
	DISC1	NM_001012957.2		c.1981+25094G>A		intron	N/A	NP_001012975.1	Q9NRI5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	ENST00000439617.8	TSL:5 MANE Select	c.1981+25094G>A		intron	N/A	ENSP00000403888.4	Q9NRI5-1
	DISC1	ENST00000366637.8	TSL:5	c.1981+25094G>A		intron	N/A	ENSP00000355597.6	Q9NRI5-2
	DISC1	ENST00000366633.7	TSL:1	c.1982-11128G>A		intron	N/A	ENSP00000355593.3	Q9NRI5-5

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99086 AN: 151984 Hom.: 32771 Cov.: 31

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.623

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

GnomAD4 genome AF: 0.652 AC: 99204 AN: 152102 Hom.: 32833 Cov.: 31 AF XY: 0.647 AC XY: 48121 AN XY: 74348

African (AFR) AF: 0.766 AC: 31777 AN: 41500

American (AMR) AF: 0.606 AC: 9272 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2375 AN: 3468

East Asian (EAS) AF: 0.602 AC: 3116 AN: 5172

South Asian (SAS) AF: 0.592 AC: 2851 AN: 4814

European-Finnish (FIN) AF: 0.588 AC: 6210 AN: 10562

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41503 AN: 67978

Other (OTH) AF: 0.626 AC: 1323 AN: 2114

Alfa AF: 0.621 Hom.: 6046

Bravo AF: 0.660

Asia WGS AF: 0.605 AC: 2107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.43
DANN	Benign	0.27
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4658954; hg19: chr1-231979357;