dbSNP rs821616: DISC1:p.Ser704Cys (chr1-232008852-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000439617.8(DISC1):c.2110A>T(p.Ser704Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,611,814 control chromosomes in the GnomAD database, including 64,018 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.29 ( 6434 hom., cov: 31)

Exomes 𝑓: 0.28 ( 57584 hom. )

Consequence

DISC1
ENST00000439617.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.17

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053812265).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3 link	c.2110A>T	p.Ser704Cys	missense_variant	Exon 11 of 13	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.2110A>T	p.Ser704Cys	missense_variant	Exon 11 of 13	5	NM_018662.3	ENSP00000403888.4		Q9NRI5-1
DISC1	ENST00000366637.8 link	c.2110A>T	p.Ser704Cys	missense_variant	Exon 11 of 13	5		ENSP00000355597.6		Q9NRI5-2

Frequencies

GnomAD3 genomes

AF:

0.285

AC:

43233

AN:

151696

Hom.:

6428

Cov.:

show subpopulations

Gnomad AFR

AF:

0.332

Gnomad AMI

AF:

0.449

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.245

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.273

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.287

Gnomad OTH

AF:

0.251

GnomAD3 exomes

AF:

0.255

AC:

62618

AN:

245122

Hom.:

8825

AF XY:

0.260

AC XY:

34624

AN XY:

133156

show subpopulations

Gnomad AFR exome

AF:

0.343

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.243

Gnomad EAS exome

AF:

0.115

Gnomad SAS exome

AF:

0.273

Gnomad FIN exome

AF:

0.331

Gnomad NFE exome

AF:

0.289

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.277

AC:

403925

AN:

1459998

Hom.:

57584

Cov.:

AF XY:

0.278

AC XY:

201633

AN XY:

726138

show subpopulations

Gnomad4 AFR exome

AF:

0.342

Gnomad4 AMR exome

AF:

0.129

Gnomad4 ASJ exome

AF:

0.239

Gnomad4 EAS exome

AF:

0.114

Gnomad4 SAS exome

AF:

0.275

Gnomad4 FIN exome

AF:

0.322

Gnomad4 NFE exome

AF:

0.286

Gnomad4 OTH exome

AF:

0.267

GnomAD4 genome

AF:

0.285

AC:

43269

AN:

151816

Hom.:

6434

Cov.:

AF XY:

0.284

AC XY:

21066

AN XY:

74174

show subpopulations

Gnomad4 AFR

AF:

0.332

Gnomad4 AMR

AF:

0.179

Gnomad4 ASJ

AF:

0.245

Gnomad4 EAS

AF:

0.121

Gnomad4 SAS

AF:

0.275

Gnomad4 FIN

AF:

0.331

Gnomad4 NFE

AF:

0.287

Gnomad4 OTH

AF:

0.255

Alfa

AF:

0.277

Hom.:

4534

Bravo

AF:

0.272

TwinsUK

AF:

0.281

AC:

1041

ALSPAC

AF:

0.294

AC:

1132

ESP6500AA

AF:

0.327

AC:

1286

ESP6500EA

AF:

0.286

AC:

2374

ExAC

AF:

0.264

AC:

31900

Asia WGS

AF:

0.217

AC:

754

AN:

3478

EpiCase

AF:

0.281

EpiControl

AF:

0.276

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Uncertain

0.98

Eigen

Benign

0.11

Eigen_PC

Benign

0.0093

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.94

PROVEAN

Benign

-0.34

REVEL

Benign

0.084

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.45

MutPred

0.25

Loss of MoRF binding (P = 0.0132);

ClinPred

0.038

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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