1-231694036-T-C

Position:

• chr1-231694036-T-C

Variant summary

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

The NM_018662.3(DISC1):​c.278T>C​(p.Leu93Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 33)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.166

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]

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=0.0451411).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DISC1	NM_018662.3	c.278T>C	p.Leu93Pro	missense_variant	2/13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.278T>C	p.Leu93Pro	missense_variant	2/13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.278T>C	p.Leu93Pro	missense_variant	2/13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.*139T>C		non_coding_transcript_exon_variant	6/13	2		ENSP00000473532.1
TSNAX-DISC1	ENST00000602956.5	n.*139T>C		3_prime_UTR_variant	6/13	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.9
DANN	Benign	0.62
DEOGEN2	Benign	0.0094	.;.;.;.;.;.;.;.;.;T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.045	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.22	N;N;N;N;.;N;N;N;N;.;.;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;N;.;N;N;N;.;N;N;.;.;N;.
REVEL	Benign	0.013
Sift	Benign	0.22	T;T;.;.;T;T;.;T;T;.;.;T;.
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0010	B;.;.;.;B;B;.;.;B;.;.;B;.
Vest4		0.11
MutPred		0.24		Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);Loss of catalytic residue at L93 (P = 0.0078);
MVP		0.21
MPC		0.18
ClinPred		0.074	T
GERP RS		1.8
Varity_R		0.062
gMVP		0.093

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-231829782;