1-231761557-A-G

Variant names:

• chr1-231761557-A-G
• rs1538977
• NM_018662.3:c.1269-5583A>G

Variant summary

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

The NM_018662.3(DISC1):​c.1269-5583A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,036 control chromosomes in the GnomAD database, including 3,259 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 0.20 (3259 hom., cov: 32)
• Consequence: DISC1 NM_018662.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.298
• Publications: 6 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3	c.1269-5583A>G		intron_variant	Intron 4 of 12	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.1269-5583A>G		intron_variant	Intron 4 of 12	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.1269-5583A>G		intron_variant	Intron 4 of 12	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.*1130-5583A>G		intron_variant	Intron 8 of 12	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30945 AN: 151918 Hom.: 3262 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.204 AC: 30945 AN: 152036 Hom.: 3259 Cov.: 32 AF XY: 0.199 AC XY: 14817 AN XY: 74332

African (AFR) AF: 0.142 AC: 5886 AN: 41478

American (AMR) AF: 0.205 AC: 3135 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3470

East Asian (EAS) AF: 0.243 AC: 1259 AN: 5172

South Asian (SAS) AF: 0.202 AC: 976 AN: 4820

European-Finnish (FIN) AF: 0.217 AC: 2291 AN: 10556

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15865 AN: 67952

Other (OTH) AF: 0.209 AC: 442 AN: 2112

Alfa AF: 0.221 Hom.: 12145

Bravo AF: 0.205

Asia WGS AF: 0.220 AC: 770 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		0.30
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: rs1538977; hg19: chr1-231897303;