chr1-231693969-G-T

Position:

chr1-231693969-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_018662.3(DISC1):c.211G>T(p.Val71Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000685 in 1,614,094 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 5 hom. )

Consequence

DISC1
NM_018662.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.544

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:

DISC1 (HGNC:):

DISC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030874312).

BP6

Variant 1-231693969-G-T is Benign according to our data. Variant chr1-231693969-G-T is described in ClinVar as [Benign]. Clinvar id is 734810.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DISC1	NM_018662.3 linkuse as main transcript	c.211G>T	p.Val71Leu	missense_variant	2/13	ENST00000439617.8	NP_061132.2	Q9NRI5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DISC1	ENST00000439617.8 linkuse as main transcript	c.211G>T	p.Val71Leu	missense_variant	2/13	5	NM_018662.3	ENSP00000403888.4	Q9NRI5-1
DISC1	ENST00000366637.8 linkuse as main transcript	c.211G>T	p.Val71Leu	missense_variant	2/13	5		ENSP00000355597.6	Q9NRI5-2
TSNAX-DISC1	ENST00000602956.5 linkuse as main transcript	n.*72G>T		non_coding_transcript_exon_variant	6/13	2		ENSP00000473532.1	C4P0D8
TSNAX-DISC1	ENST00000602956.5 linkuse as main transcript	n.*72G>T		3_prime_UTR_variant	6/13	2		ENSP00000473532.1	C4P0D8

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

527

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000951

AC:

236

AN:

248040

Hom.:

AF XY:

0.000744

AC XY:

100

AN XY:

134364

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.000985

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000687

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000451

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000393

AC:

575

AN:

1461758

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

273

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.0110

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000626

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00349

AC:

531

AN:

152336

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0120

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.00396

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00117

AC:

142

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2018

- -

DISC1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2019

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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.7

DANN

Benign

0.18

DEOGEN2

Benign

0.0056

.;.;.;.;.;.;.;.;.;T;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.72

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0031

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N;N;N;.;N;N;N;N;.;.;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.41

N;N;.;N;N;N;.;N;N;.;.;N;.

REVEL

Benign

0.021

Sift

Benign

0.89

T;T;.;.;T;T;.;T;T;.;.;T;.

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T;T;T;.

Polyphen

0.0

B;.;.;.;B;B;.;.;B;.;.;B;.

Vest4

0.038

MutPred

0.091

Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);

MVP

0.13

MPC

0.11

ClinPred

0.0016

GERP RS

-0.44

Varity_R

0.033

gMVP

0.092

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over