chr1-231626907-G-A

Position:

• chr1-231626907-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018662.3(DISC1):​c.40G>A​(p.Gly14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 1,344,090 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G14R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.383

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

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=0.15934733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DISC1	NM_018662.3	c.40G>A	p.Gly14Ser	missense_variant	1/13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.40G>A	p.Gly14Ser	missense_variant	1/13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.40G>A	p.Gly14Ser	missense_variant	1/13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.495+65652G>A		intron_variant		2		ENSP00000473532.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000298 AC: 4 AN: 1344090 Hom.: 0 Cov.: 30 AF XY: 0.00000301 AC XY: 2 AN XY: 663388

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: 0.00000377

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2024

The c.40G>A (p.G14S) alteration is located in exon 1 (coding exon 1) of the DISC1 gene. This alteration results from a G to A substitution at nucleotide position 40, causing the glycine (G) at amino acid position 14 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	Benign	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.3
DANN	Benign	0.84
DEOGEN2	Benign	0.0090	.;.;.;.;.;.;.;.;.;.;T;.;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.58	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N;N;N;.;N;N;N;N;.;.;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.48	N;.;N;.;N;N;N;.;N;N;.;.;N;.
REVEL	Benign	0.13
Sift	Benign	0.092	T;.;D;.;.;T;D;.;D;D;.;.;D;.
Sift4G	Benign	0.65	T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		1.0	D;.;.;.;.;.;D;.;.;D;.;.;D;.
Vest4		0.18
MutPred		0.16		Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);Gain of glycosylation at G14 (P = 0.0014);
MVP		0.51
MPC		0.11
ClinPred		0.15	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.025
gMVP		0.11

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

Other links and lift over

dbSNP: rs1011857318; hg19: chr1-231762653;