1-231693969-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018662.3(DISC1):c.211G>T(p.Val71Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000685 in 1,614,094 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.544

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:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030874312).
• BP6: Variant 1-231693969-G-T is Benign according to our data. Variant chr1-231693969-G-T is described in ClinVar as [Benign]. Clinvar id is 734810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DISC1	NM_018662.3	c.211G>T	p.Val71Leu	missense_variant	2/13	ENST00000439617.8
TSNAX-DISC1	NR_028393.1	n.932G>T		non_coding_transcript_exon_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DISC1	ENST00000439617.8	c.211G>T	p.Val71Leu	missense_variant	2/13	5	NM_018662.3	A2

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000951 AC: 236 AN: 248040 Hom.: 2 AF XY: 0.000744 AC XY: 100 AN XY: 134364

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000687

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000451

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000393 AC: 575 AN: 1461758 Hom.: 5 Cov.: 32 AF XY: 0.000375 AC XY: 273 AN XY: 727168

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00353 AC XY: 263 AN XY: 74492

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00396

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2018

- -

DISC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2019

This variant is classified as 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	0.11
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	1.7
Dann	Benign	0.18
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.72	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;N;N;.;N;N;N;N;.;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.41	N;N;.;N;N;N;.;N;N;.;.;N;.
REVEL	Benign	0.021
Sift	Benign	0.89	T;T;.;.;T;T;.;T;T;.;.;T;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;.;.;.;B;B;.;.;B;.;.;B;.
Vest4		0.038
MutPred		0.091		Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);Loss of glycosylation at S72 (P = 0.125);
MVP		0.13
MPC		0.11
ClinPred		0.0016	T
GERP RS		-0.44
Varity_R		0.033
gMVP		0.092

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: rs149444280; hg19: chr1-231829715;