rs12133766

Variant names:

• chr1-231818399-G-A
• rs12133766
• NM_018662.3:c.1863G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_018662.3(DISC1):​c.1863G>A​(p.Leu621Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,614,106 control chromosomes in the GnomAD database, including 2,695 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 0.046 (188 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2507 hom.)
• Consequence: DISC1 NM_018662.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.46
• Publications: 26 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:):

DISC2 (HGNC:2889): (disrupted in schizophrenia 2) DISC2 is thought to specify a noncoding RNA molecule antisense to DISC1 (MIM 605210). Both genes were found to be disrupted by a translocation in a large schizophrenia (MIM 181500) kindred.[supplied by OMIM, Jul 2002]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=3.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3	c.1863G>A	p.Leu621Leu	synonymous_variant	Exon 9 of 13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.1863G>A	p.Leu621Leu	synonymous_variant	Exon 9 of 13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.1863G>A	p.Leu621Leu	synonymous_variant	Exon 9 of 13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.*1724G>A		non_coding_transcript_exon_variant	Exon 13 of 13	2		ENSP00000473532.1
TSNAX-DISC1	ENST00000602956.5	n.*1724G>A		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6975 AN: 152168 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0463

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.0327

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.0663

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0576

Gnomad OTH AF: 0.0527

GnomAD2 exomes AF: 0.0502 AC: 12616 AN: 251278 AF XY: 0.0525

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0833

Gnomad EAS exome AF: 0.0293

Gnomad FIN exome AF: 0.0577

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0558 AC: 81611 AN: 1461820 Hom.: 2507 Cov.: 31 AF XY: 0.0563 AC XY: 40928 AN XY: 727220

African (AFR) AF: 0.0174 AC: 583 AN: 33476

American (AMR) AF: 0.0292 AC: 1304 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 2289 AN: 26134

East Asian (EAS) AF: 0.0231 AC: 919 AN: 39700

South Asian (SAS) AF: 0.0464 AC: 4004 AN: 86254

European-Finnish (FIN) AF: 0.0543 AC: 2903 AN: 53420

Middle Eastern (MID) AF: 0.0796 AC: 459 AN: 5768

European-Non Finnish (NFE) AF: 0.0590 AC: 65604 AN: 1111962

Other (OTH) AF: 0.0587 AC: 3546 AN: 60388

GnomAD4 genome AF: 0.0458 AC: 6981 AN: 152286 Hom.: 188 Cov.: 33 AF XY: 0.0462 AC XY: 3444 AN XY: 74474

African (AFR) AF: 0.0184 AC: 765 AN: 41552

American (AMR) AF: 0.0462 AC: 707 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0919 AC: 319 AN: 3472

East Asian (EAS) AF: 0.0328 AC: 170 AN: 5184

South Asian (SAS) AF: 0.0520 AC: 251 AN: 4824

European-Finnish (FIN) AF: 0.0663 AC: 703 AN: 10610

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0576 AC: 3919 AN: 68024

Other (OTH) AF: 0.0521 AC: 110 AN: 2110

Alfa AF: 0.0579 Hom.: 540

Bravo AF: 0.0436

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.0667

EpiControl AF: 0.0652

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.0
DANN	Benign	0.78
PhyloP100		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=299/1	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: rs12133766; hg19: chr1-231954145; COSMIC: COSV54403519; COSMIC: COSV54403519;