rs77080351

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-231694792-G-A
• chr1-231694792-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018662.3(DISC1):​c.1034G>A​(p.Arg345Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,613,626 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R345W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00063 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (8 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.683
• Publications: 4 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003768593).
• BP6: Variant 1-231694792-G-A is Benign according to our data. Variant chr1-231694792-G-A is described in ClinVar as Benign. ClinVar VariationId is 713043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1034G>A	p.Arg345Gln	missense	Exon 2 of 13	NP_061132.2
	DISC1	NM_001164537.2		c.1034G>A	p.Arg345Gln	missense	Exon 2 of 14	NP_001158009.1
	DISC1	NM_001012957.2		c.1034G>A	p.Arg345Gln	missense	Exon 2 of 13	NP_001012975.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	ENST00000439617.8	TSL:5 MANE Select	c.1034G>A	p.Arg345Gln	missense	Exon 2 of 13	ENSP00000403888.4
	DISC1	ENST00000366637.8	TSL:5	c.1034G>A	p.Arg345Gln	missense	Exon 2 of 13	ENSP00000355597.6
	DISC1	ENST00000366633.7	TSL:1	c.1034G>A	p.Arg345Gln	missense	Exon 2 of 10	ENSP00000355593.3

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152222 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00128 AC: 313 AN: 244916 AF XY: 0.00111

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0163

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000421 AC: 615 AN: 1461286 Hom.: 8 Cov.: 34 AF XY: 0.000382 AC XY: 278 AN XY: 726938

African (AFR) AF: 0.000209 AC: 7 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44696

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

East Asian (EAS) AF: 0.0123 AC: 490 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86204

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52980

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111960

Other (OTH) AF: 0.00137 AC: 83 AN: 60378

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152340 Hom.: 2 Cov.: 33 AF XY: 0.000644 AC XY: 48 AN XY: 74496

African (AFR) AF: 0.000144 AC: 6 AN: 41586

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0157 AC: 81 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000744 Hom.: 2

Bravo AF: 0.000824

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.084
DANN	Benign	0.91
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.68
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.086
Sift	Benign	0.23	T
Sift4G	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.14
MVP		0.23
MPC		0.16
ClinPred		0.0027	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.016
gMVP		0.27
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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; COSMIC: COSV54400122; COSMIC: COSV54400122;