1-231694549-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018662.3(DISC1):c.791G>A(p.Arg264Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,978 control chromosomes in the GnomAD database, including 77,384 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.26 ( 5671 hom., cov: 33)

Exomes 𝑓: 0.31 ( 71713 hom. )

Consequence

DISC1
NM_018662.3 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -1.13

Publications

102 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018889904).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.316 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DISC1	NM_018662.3	MANE Select	c.791G>A	p.Arg264Gln	missense	Exon 2 of 13	NP_061132.2	Q9NRI5-1
DISC1	NM_001164537.2		c.791G>A	p.Arg264Gln	missense	Exon 2 of 14	NP_001158009.1	C4P096
DISC1	NM_001012957.2		c.791G>A	p.Arg264Gln	missense	Exon 2 of 13	NP_001012975.1	Q9NRI5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DISC1	ENST00000439617.8	TSL:5 MANE Select	c.791G>A	p.Arg264Gln	missense	Exon 2 of 13	ENSP00000403888.4	Q9NRI5-1
DISC1	ENST00000366637.8	TSL:5	c.791G>A	p.Arg264Gln	missense	Exon 2 of 13	ENSP00000355597.6	Q9NRI5-2
DISC1	ENST00000366633.7	TSL:1	c.791G>A	p.Arg264Gln	missense	Exon 2 of 10	ENSP00000355593.3	Q9NRI5-5

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39622

AN:

152140

Hom.:

5672

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.178

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.289

Gnomad EAS

AF:

0.238

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.283

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.303

GnomAD2 exomes

AF:

0.296

AC:

73630

AN:

248600

AF XY:

0.295

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.244

Gnomad FIN exome

AF:

0.287

Gnomad NFE exome

AF:

0.317

Gnomad OTH exome

AF:

0.318

GnomAD4 exome

AF:

0.311

AC:

454502

AN:

1461716

Hom.:

71713

Cov.:

AF XY:

0.309

AC XY:

225018

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.135

AC:

4513

AN:

33480

American (AMR)

AF:

0.355

AC:

15872

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.306

AC:

8000

AN:

26136

East Asian (EAS)

AF:

0.250

AC:

9915

AN:

39700

South Asian (SAS)

AF:

0.266

AC:

22943

AN:

86256

European-Finnish (FIN)

AF:

0.290

AC:

15471

AN:

53350

Middle Eastern (MID)

AF:

0.284

AC:

1640

AN:

5768

European-Non Finnish (NFE)

AF:

0.322

AC:

357960

AN:

1111930

Other (OTH)

AF:

0.301

AC:

18188

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

23807

47614

71420

95227

119034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11580

23160

34740

46320

57900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.260

AC:

39633

AN:

152262

Hom.:

5671

Cov.:

AF XY:

0.257

AC XY:

19116

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.140

AC:

5802

AN:

41586

American (AMR)

AF:

0.316

AC:

4829

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

1004

AN:

3472

East Asian (EAS)

AF:

0.237

AC:

1228

AN:

5176

South Asian (SAS)

AF:

0.240

AC:

1157

AN:

4826

European-Finnish (FIN)

AF:

0.283

AC:

2989

AN:

10576

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.320

AC:

21738

AN:

68010

Other (OTH)

AF:

0.304

AC:

642

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1529

3058

4588

6117

7646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

416

832

1248

1664

2080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.300

Hom.:

27270

Bravo

AF:

0.260

TwinsUK

AF:

0.320

AC:

1187

ALSPAC

AF:

0.311

AC:

1199

ESP6500AA

AF:

0.147

AC:

648

ESP6500EA

AF:

0.318

AC:

2734

ExAC

AF:

0.292

AC:

35430

Asia WGS

AF:

0.233

AC:

814

AN:

3478

EpiCase

AF:

0.316

EpiControl

AF:

0.319

ClinVar

ClinVar submissions

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.051

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0097

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0072

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.86

PhyloP100

-1.1

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.11

REVEL

Benign

0.028

Sift

Benign

0.39

Sift4G

Benign

0.43

Polyphen

0.0010

Vest4

0.010

MPC

0.13

ClinPred

0.016

GERP RS

-9.9

Varity_R

0.021

gMVP

0.060

Mutation Taster

=286/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over