rs3738402

Variant names:

• chr1-231767264-C-T
• rs3738402
• NM_018662.3:c.1393C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_018662.3(DISC1):​c.1393C>T​(p.Leu465Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0451 in 1,614,068 control chromosomes in the GnomAD database, including 3,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.051 (373 hom., cov: 33)
  • Exomes 𝑓: 0.044 (3012 hom.)
• Consequence: DISC1 NM_018662.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.766
• Publications: 19 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:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-231767264-C-T is Benign according to our data. Variant chr1-231767264-C-T is described in ClinVar as Benign. ClinVar VariationId is 3059485.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.766 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3	c.1393C>T	p.Leu465Leu	synonymous_variant	Exon 5 of 13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.1393C>T	p.Leu465Leu	synonymous_variant	Exon 5 of 13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.1393C>T	p.Leu465Leu	synonymous_variant	Exon 5 of 13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.*1254C>T		non_coding_transcript_exon_variant	Exon 9 of 13	2		ENSP00000473532.1
TSNAX-DISC1	ENST00000602956.5	n.*1254C>T		3_prime_UTR_variant	Exon 9 of 13	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7779 AN: 152102 Hom.: 377 Cov.: 33

Gnomad AFR AF: 0.0461

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.0836

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.0589

GnomAD2 exomes AF: 0.0756 AC: 18806 AN: 248802 AF XY: 0.0695

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.210

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0316

Gnomad OTH exome AF: 0.0571

GnomAD4 exome AF: 0.0444 AC: 64949 AN: 1461848 Hom.: 3012 Cov.: 31 AF XY: 0.0443 AC XY: 32204 AN XY: 727234

African (AFR) AF: 0.0487 AC: 1629 AN: 33480

American (AMR) AF: 0.194 AC: 8667 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0203 AC: 530 AN: 26136

East Asian (EAS) AF: 0.223 AC: 8869 AN: 39700

South Asian (SAS) AF: 0.0723 AC: 6238 AN: 86258

European-Finnish (FIN) AF: 0.0324 AC: 1730 AN: 53410

Middle Eastern (MID) AF: 0.0373 AC: 215 AN: 5768

European-Non Finnish (NFE) AF: 0.0306 AC: 34041 AN: 1111988

Other (OTH) AF: 0.0502 AC: 3030 AN: 60392

GnomAD4 genome AF: 0.0510 AC: 7767 AN: 152220 Hom.: 373 Cov.: 33 AF XY: 0.0533 AC XY: 3968 AN XY: 74416

African (AFR) AF: 0.0459 AC: 1909 AN: 41552

American (AMR) AF: 0.113 AC: 1729 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3468

East Asian (EAS) AF: 0.220 AC: 1133 AN: 5150

South Asian (SAS) AF: 0.0825 AC: 397 AN: 4814

European-Finnish (FIN) AF: 0.0294 AC: 312 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0295 AC: 2005 AN: 68014

Other (OTH) AF: 0.0587 AC: 124 AN: 2112

Alfa AF: 0.0421 Hom.: 709

Bravo AF: 0.0620

Asia WGS AF: 0.145 AC: 505 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0294

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DISC1-related disorder Benign:1

Apr 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.70
PhyloP100		-0.77
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: rs3738402; hg19: chr1-231903010; COSMIC: COSV54418037;