Genetic Variant DISC1:c.-7G>T (chr1-231626861-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018662.3(DISC1):c.-7G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000231 in 1,297,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 31)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

DISC1
NM_018662.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.669

Publications

6 publications found

Variant links:

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]

DISC1 links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3 link	c.-7G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 13	ENST00000439617.8	NP_061132.2
DISC1	NM_018662.3 link	c.-7G>T		5_prime_UTR_variant	Exon 1 of 13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
DISC1	ENST00000439617.8 link	c.-7G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8 link	c.-7G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 13	5		ENSP00000355597.6
DISC1	ENST00000439617.8 link	c.-7G>T	5_prime_UTR_variant	Exon 1 of 13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8 link	c.-7G>T	5_prime_UTR_variant	Exon 1 of 13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5 link	n.495+65606G>T	intron_variant	Intron 5 of 12	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000181

AC:

AN:

55326

AF XY:

0.0000314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000231

AC:

AN:

1297894

Hom.:

Cov.:

AF XY:

0.00000470

AC XY:

AN XY:

638286

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25194

American (AMR)

AF:

0.00

AC:

AN:

19060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20088

East Asian (EAS)

AF:

0.00

AC:

AN:

31672

South Asian (SAS)

AF:

0.0000447

AC:

AN:

67054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1045732

Other (OTH)

AF:

0.00

AC:

AN:

53706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.5

(source)

DANN

Benign

0.64

PhyloP100

-0.67

PromoterAI

-0.063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Mutation Taster

=300/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over