Genetic Variant DISC1:c.*250A>G (chr1-232009141-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001164538.2(DISC1):c.2399A>G(p.Lys800Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,575,808 control chromosomes in the GnomAD database, including 62,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 6466 hom., cov: 31)

Exomes 𝑓: 0.28 ( 56278 hom. )

Consequence

DISC1
NM_001164538.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.351

Variant links:

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]

DISC1 links:

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]

TSNAX-DISC1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3 link	c.2307+92A>G		intron_variant	Intron 11 of 12	ENST00000439617.8	NP_061132.2	Q9NRI5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8 link	c.2307+92A>G		intron_variant	Intron 11 of 12	5	NM_018662.3	ENSP00000403888.4		Q9NRI5-1
DISC1	ENST00000366637.8 link	c.2241+158A>G		intron_variant	Intron 11 of 12	5		ENSP00000355597.6		Q9NRI5-2

Frequencies

GnomAD3 genomes

AF:

0.285

AC:

43312

AN:

151778

Hom.:

6460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.333

Gnomad AMI

AF:

0.450

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.243

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.273

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.288

Gnomad OTH

AF:

0.252

GnomAD3 exomes

AF:

0.259

AC:

52882

AN:

204542

Hom.:

7343

AF XY:

0.263

AC XY:

28794

AN XY:

109522

show subpopulations

Gnomad AFR exome

AF:

0.348

Gnomad AMR exome

AF:

0.124

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.116

Gnomad SAS exome

AF:

0.276

Gnomad FIN exome

AF:

0.333

Gnomad NFE exome

AF:

0.293

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.277

AC:

394268

AN:

1423912

Hom.:

56278

Cov.:

AF XY:

0.278

AC XY:

195492

AN XY:

703868

show subpopulations

Gnomad4 AFR exome

AF:

0.341

Gnomad4 AMR exome

AF:

0.129

Gnomad4 ASJ exome

AF:

0.236

Gnomad4 EAS exome

AF:

0.114

Gnomad4 SAS exome

AF:

0.274

Gnomad4 FIN exome

AF:

0.322

Gnomad4 NFE exome

AF:

0.286

Gnomad4 OTH exome

AF:

0.266

GnomAD4 genome

AF:

0.285

AC:

43346

AN:

151896

Hom.:

6466

Cov.:

AF XY:

0.284

AC XY:

21106

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.332

Gnomad4 AMR

AF:

0.179

Gnomad4 ASJ

AF:

0.243

Gnomad4 EAS

AF:

0.121

Gnomad4 SAS

AF:

0.274

Gnomad4 FIN

AF:

0.331

Gnomad4 NFE

AF:

0.288

Gnomad4 OTH

AF:

0.256

Alfa

AF:

0.274

Hom.:

5063

Bravo

AF:

0.272

Asia WGS

AF:

0.216

AC:

752

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

5.6

DANN

Benign

0.52

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over