1-231626881-G-A

Variant names:

• chr1-231626881-G-A
• rs3738400
• NM_018662.3:c.14G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018662.3(DISC1):​c.14G>A​(p.Gly5Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000749 in 1,334,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.706
• Publications: 1 publications found

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14387196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3	c.14G>A	p.Gly5Asp	missense_variant	Exon 1 of 13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.14G>A	p.Gly5Asp	missense_variant	Exon 1 of 13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.14G>A	p.Gly5Asp	missense_variant	Exon 1 of 13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.495+65626G>A		intron_variant	Intron 5 of 12	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.49e-7 AC: 1 AN: 1334486 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 658630

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26442

American (AMR) AF: 0.00 AC: 0 AN: 26226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22730

East Asian (EAS) AF: 0.0000308 AC: 1 AN: 32484

South Asian (SAS) AF: 0.00 AC: 0 AN: 74062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3882

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1060536

Other (OTH) AF: 0.00 AC: 0 AN: 55334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.72
DEOGEN2	Benign	0.011	.;.;.;.;.;.;.;.;.;.;T;.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.61	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;N;N;N;.;N;N;N;N;.;.;N;N
PhyloP100		0.71
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N;.;N;.;N;N;N;.;N;N;.;.;N;.
REVEL	Benign	0.065
Sift	Pathogenic	0.0	D;.;D;.;.;D;D;.;D;D;.;.;D;.
Sift4G	Benign	0.11	T;.;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.93	P;.;.;.;.;.;P;.;.;P;.;.;P;.
Vest4		0.30
MutPred		0.21		Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);Loss of catalytic residue at G5 (P = 0.0225);
MVP		0.65
MPC		0.14
ClinPred		0.19	T
GERP RS		1.2
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.081
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs3738400; hg19: chr1-231762627;