rs821616

Variant names:

• chr1-232008852-A-T
• rs821616
• NM_018662.3:c.2110A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018662.3(DISC1):​c.2110A>T​(p.Ser704Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,611,814 control chromosomes in the GnomAD database, including 64,018 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 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: 𝑓 0.29 (6434 hom., cov: 31)
  • Exomes 𝑓: 0.28 (57584 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17
• Publications: 182 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053812265).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3	c.2110A>T	p.Ser704Cys	missense_variant	Exon 11 of 13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.2110A>T	p.Ser704Cys	missense_variant	Exon 11 of 13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.2110A>T	p.Ser704Cys	missense_variant	Exon 11 of 13	5		ENSP00000355597.6

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43233 AN: 151696 Hom.: 6428 Cov.: 31

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.251

GnomAD2 exomes AF: 0.255 AC: 62618 AN: 245122 AF XY: 0.260

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.331

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.277 AC: 403925 AN: 1459998 Hom.: 57584 Cov.: 34 AF XY: 0.278 AC XY: 201633 AN XY: 726138

African (AFR) AF: 0.342 AC: 11399 AN: 33358

American (AMR) AF: 0.129 AC: 5761 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6212 AN: 26012

East Asian (EAS) AF: 0.114 AC: 4525 AN: 39684

South Asian (SAS) AF: 0.275 AC: 23693 AN: 86138

European-Finnish (FIN) AF: 0.322 AC: 17149 AN: 53322

Middle Eastern (MID) AF: 0.259 AC: 1489 AN: 5760

European-Non Finnish (NFE) AF: 0.286 AC: 317631 AN: 1110866

Other (OTH) AF: 0.267 AC: 16066 AN: 60278

GnomAD4 genome AF: 0.285 AC: 43269 AN: 151816 Hom.: 6434 Cov.: 31 AF XY: 0.284 AC XY: 21066 AN XY: 74174

African (AFR) AF: 0.332 AC: 13724 AN: 41358

American (AMR) AF: 0.179 AC: 2731 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 849 AN: 3470

East Asian (EAS) AF: 0.121 AC: 621 AN: 5140

South Asian (SAS) AF: 0.275 AC: 1322 AN: 4816

European-Finnish (FIN) AF: 0.331 AC: 3485 AN: 10514

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19525 AN: 67962

Other (OTH) AF: 0.255 AC: 537 AN: 2102

Alfa AF: 0.277 Hom.: 4534

Bravo AF: 0.272

TwinsUK AF: 0.281 AC: 1041

ALSPAC AF: 0.294 AC: 1132

ESP6500AA AF: 0.327 AC: 1286

ESP6500EA AF: 0.286 AC: 2374

ExAC AF: 0.264 AC: 31900

Asia WGS AF: 0.217 AC: 754 AN: 3478

EpiCase AF: 0.281

EpiControl AF: 0.276

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	23
DANN	Uncertain	0.98
Eigen	Benign	0.11
Eigen_PC	Benign	0.0093
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.94	T
PhyloP100		3.2
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.45
MutPred		0.25		Loss of MoRF binding (P = 0.0132);
ClinPred		0.038	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs821616; hg19: chr1-232144598; COSMIC: COSV64093108;