1-231694792-G-C

Variant names:

• chr1-231694792-G-C
• rs77080351
• NM_018662.3:c.1034G>C

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.1034G>C​(p.Arg345Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R345Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.683
• 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=0.25923395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3	c.1034G>C	p.Arg345Pro	missense_variant	Exon 2 of 13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.1034G>C	p.Arg345Pro	missense_variant	Exon 2 of 13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.1034G>C	p.Arg345Pro	missense_variant	Exon 2 of 13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.*895G>C		non_coding_transcript_exon_variant	Exon 6 of 13	2		ENSP00000473532.1
TSNAX-DISC1	ENST00000602956.5	n.*895G>C		3_prime_UTR_variant	Exon 6 of 13	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461286 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726938

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.0
DANN	Benign	0.71
DEOGEN2	Benign	0.20	.;.;.;.;.;.;.;.;.;T;.;D;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.037	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;T;T;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.;M;M;M;M;.;.;M;M
PhyloP100		-0.68
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-4.0	D;D;.;D;D;D;.;D;D;.;.;D;.
REVEL	Benign	0.22
Sift	Benign	0.045	D;D;.;.;D;D;.;D;D;.;.;D;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.85	P;.;.;.;D;D;.;.;D;.;.;D;.
Vest4		0.51
MutPred		0.61		Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);
MVP		0.40
MPC		0.63
ClinPred		0.67	D
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.14
gMVP		0.70
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs77080351; hg19: chr1-231830538;