chr1-231626907-G-A

Variant names:

• chr1-231626907-G-A
• rs1011857318
• NM_018662.3:c.40G>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.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. 15/22 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
• Publications: 0 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=0.15934733).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018662.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	NM_018662.3	MANE Select	c.40G>A	p.Gly14Ser	missense	Exon 1 of 13	NP_061132.2	Q9NRI5-1
	DISC1	NM_001164537.2		c.40G>A	p.Gly14Ser	missense	Exon 1 of 14	NP_001158009.1	C4P096
	DISC1	NM_001012957.2		c.40G>A	p.Gly14Ser	missense	Exon 1 of 13	NP_001012975.1	Q9NRI5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	ENST00000439617.8	TSL:5 MANE Select	c.40G>A	p.Gly14Ser	missense	Exon 1 of 13	ENSP00000403888.4	Q9NRI5-1
	DISC1	ENST00000366637.8	TSL:5	c.40G>A	p.Gly14Ser	missense	Exon 1 of 13	ENSP00000355597.6	Q9NRI5-2
	DISC1	ENST00000366633.7	TSL:1	c.40G>A	p.Gly14Ser	missense	Exon 1 of 10	ENSP00000355593.3	Q9NRI5-5

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

African (AFR) AF: 0.00 AC: 0 AN: 27234

American (AMR) AF: 0.00 AC: 0 AN: 29548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23686

East Asian (EAS) AF: 0.00 AC: 0 AN: 32586

South Asian (SAS) AF: 0.00 AC: 0 AN: 75642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4188

European-Non Finnish (NFE) AF: 0.00000377 AC: 4 AN: 1062306

Other (OTH) AF: 0.00 AC: 0 AN: 55838

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.38
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.13
Sift	Benign	0.092	T
Sift4G	Benign	0.65	T
Polyphen		1.0	D
Vest4		0.18
MutPred		0.16		Gain of glycosylation at G14 (P = 0.0014)
MVP		0.51
MPC		0.11
ClinPred		0.15	T
GERP RS		2.4
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.025
gMVP		0.11
Mutation Taster		=92/8	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: rs1011857318; hg19: chr1-231762653;