1-231694269-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018662.3(DISC1):c.511G>A(p.Val171Ile) 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 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.204

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044731796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DISC1	NM_018662.3	c.511G>A	p.Val171Ile	missense_variant	2/13	ENST00000439617.8
TSNAX-DISC1	NR_028393.1	n.1232G>A		non_coding_transcript_exon_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DISC1	ENST00000439617.8	c.511G>A	p.Val171Ile	missense_variant	2/13	5	NM_018662.3	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248784 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.511G>A (p.V171I) alteration is located in exon 2 (coding exon 2) of the DISC1 gene. This alteration results from a G to A substitution at nucleotide position 511, causing the valine (V) at amino acid position 171 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.038
Dann	Benign	0.63
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.045	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	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	0.27	T
PROVEAN	Benign	-0.43	N;N;.;N;N;N;.;N;N;.;.;N;.
REVEL	Benign	0.0090
Sift	Benign	0.28	T;T;.;.;T;T;.;T;T;.;.;T;.
Sift4G	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;.;.;.;B;B;.;.;B;.;.;B;.
Vest4		0.045
MutPred		0.15		Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);Loss of methylation at R172 (P = 0.0586);
MVP		0.076
MPC		0.092
ClinPred		0.12	T
GERP RS		-7.3
Varity_R		0.012
gMVP		0.047

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: rs768544712; hg19: chr1-231830015; COSMIC: COSV99697679; COSMIC: COSV99697679;