chr1-231626907-G-C

Position:

chr1-231626907-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018662.3(DISC1):c.40G>C(p.Gly14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000134 in 1,494,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G14G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

DISC1
NM_018662.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.383

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:

TSNAX-DISC1 (HGNC:):

TSNAX-DISC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15804708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DISC1	NM_018662.3 linkuse as main transcript	c.40G>C	p.Gly14Arg	missense_variant	1/13	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.40G>C	p.Gly14Arg	missense_variant	1/13	5	NM_018662.3	ENSP00000403888.4	Q9NRI5-1
DISC1	ENST00000366637.8 linkuse as main transcript	c.40G>C	p.Gly14Arg	missense_variant	1/13	5		ENSP00000355597.6	Q9NRI5-2
TSNAX-DISC1	ENST00000602956.5 linkuse as main transcript	n.495+65652G>C		intron_variant		2		ENSP00000473532.1	C4P0D8

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000101

AC:

AN:

98844

Hom.:

AF XY:

0.00

AC XY:

AN XY:

55758

show subpopulations

Gnomad AFR exome

AF:

0.000503

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.44e-7

AC:

AN:

1344090

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

663388

show subpopulations

Gnomad4 AFR exome

AF:

0.0000367

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150856

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73630

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

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

May 26, 2024

The c.40G>C (p.G14R) alteration is located in exon 1 (coding exon 1) of the DISC1 gene. This alteration results from a G to C substitution at nucleotide position 40, causing the glycine (G) at amino acid position 14 to be replaced by an arginine (R). 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

Benign

0.31

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.34

CADD

Benign

6.0

DANN

Benign

0.94

DEOGEN2

Benign

0.0099

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

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.68

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

M_CAP

Benign

0.0056

MetaRNN

Benign

0.16

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.4

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

REVEL

Benign

0.14

Sift

Uncertain

0.022

D;.;D;.;.;T;D;.;D;D;.;.;D;.

Sift4G

Benign

0.20

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

Polyphen

1.0

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

Vest4

0.24

MutPred

0.28

Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);Gain of methylation at G14 (P = 0.0019);

MVP

0.62

MPC

0.13

ClinPred

0.11

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.032

gMVP

0.12

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