1-231626905-C-G

Position:

• chr1-231626905-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_018662.3(DISC1):​c.38C>G​(p.Ala13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,502,518 control chromosomes in the GnomAD database, including 11 homozygotes. 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0039 (9 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.23

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]

TSNAX-DISC1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063332915).
• BP6: Variant 1-231626905-C-G is Benign according to our data. Variant chr1-231626905-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3055850.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DISC1	NM_018662.3	c.38C>G	p.Ala13Gly	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.38C>G	p.Ala13Gly	missense_variant	1/13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.38C>G	p.Ala13Gly	missense_variant	1/13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.495+65650C>G		intron_variant		2		ENSP00000473532.1

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 420 AN: 151710 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00423

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00238 AC: 238 AN: 99868 Hom.: 0 AF XY: 0.00217 AC XY: 122 AN XY: 56300

Gnomad AFR exome AF: 0.000484

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.00599

Gnomad EAS exome AF: 0.000455

Gnomad SAS exome AF: 0.000154

Gnomad FIN exome AF: 0.000599

Gnomad NFE exome AF: 0.00425

Gnomad OTH exome AF: 0.000650

GnomAD4 exome AF: 0.00387 AC: 5226 AN: 1350698 Hom.: 9 Cov.: 30 AF XY: 0.00371 AC XY: 2474 AN XY: 666646

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.000925

Gnomad4 ASJ exome AF: 0.00531

Gnomad4 EAS exome AF: 0.000121

Gnomad4 SAS exome AF: 0.000236

Gnomad4 FIN exome AF: 0.000482

Gnomad4 NFE exome AF: 0.00457

Gnomad4 OTH exome AF: 0.00223

GnomAD4 genome AF: 0.00277 AC: 420 AN: 151820 Hom.: 2 Cov.: 31 AF XY: 0.00256 AC XY: 190 AN XY: 74182

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00423

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00294 Hom.: 1

Bravo AF: 0.00269

ExAC AF: 0.000748 AC: 11

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DISC1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.056
DANN	Benign	0.26
DEOGEN2	Benign	0.013	.;.;.;.;.;.;.;.;.;.;T;.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00051	N
LIST_S2	Benign	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.0063	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N;N;.;N;N;N;N;.;.;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.76	N;.;N;.;N;N;N;.;N;N;.;.;N;.
REVEL	Benign	0.016
Sift	Benign	0.059	T;.;T;.;.;T;T;.;T;T;.;.;T;.
Sift4G	Benign	0.29	T;D;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;.;.;.;.;.;B;.;.;B;.;.;B;.
Vest4		0.12
MVP		0.20
MPC		0.11
ClinPred		0.0019	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.15

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: rs79978593; hg19: chr1-231762651; COSMIC: COSV105140653; COSMIC: COSV105140653;