chr1-231693919-T-G

Position:

chr1-231693919-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018662.3(DISC1):c.161T>G(p.Ile54Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DISC1
NM_018662.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.996

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28783643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DISC1	NM_018662.3 linkuse as main transcript	c.161T>G	p.Ile54Ser	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.161T>G	p.Ile54Ser	missense_variant	2/13	5	NM_018662.3	ENSP00000403888.4	Q9NRI5-1
DISC1	ENST00000366637.8 linkuse as main transcript	c.161T>G	p.Ile54Ser	missense_variant	2/13	5		ENSP00000355597.6	Q9NRI5-2
TSNAX-DISC1	ENST00000602956.5 linkuse as main transcript	n.*22T>G		non_coding_transcript_exon_variant	6/13	2		ENSP00000473532.1	C4P0D8
TSNAX-DISC1	ENST00000602956.5 linkuse as main transcript	n.*22T>G		3_prime_UTR_variant	6/13	2		ENSP00000473532.1	C4P0D8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248842

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.161T>G (p.I54S) alteration is located in exon 2 (coding exon 2) of the DISC1 gene. This alteration results from a T to G substitution at nucleotide position 161, causing the isoleucine (I) at amino acid position 54 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

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

Eigen

Benign

0.093

Eigen_PC

Benign

-0.028

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.29

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;M;M;M;.;M;M;M;M;.;.;M;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-5.1

D;N;.;N;D;N;.;N;N;.;.;N;.

REVEL

Benign

0.16

Sift

Uncertain

0.0010

D;D;.;.;D;D;.;D;D;.;.;D;.

Sift4G

Uncertain

0.017

D;D;D;D;D;D;D;D;D;D;D;D;.

Polyphen

1.0

D;.;.;.;D;D;.;.;D;.;.;D;.

Vest4

0.56

MutPred

0.31

Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);Gain of glycosylation at I54 (P = 0.0011);

MVP

0.47

MPC

0.64

ClinPred

0.97

GERP RS

3.7

Varity_R

0.16

gMVP

0.49

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