ENST00000422590.6:n.-7G>A

Variant names:

• chr1-231626830-C-A
• NM_018662.3:c.-38C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000422590.6(DISC1):​n.-38C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000793 in 1,260,558 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: 7.9e-7 (0 hom.)
• Consequence: DISC1 ENST00000422590.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.156
• Publications: 0 publications found

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]

ACMG classification

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=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000422590.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	NM_018662.3	MANE Select	c.-38C>A		5_prime_UTR	Exon 1 of 13	NP_061132.2
	DISC1	NM_001164537.2		c.-38C>A		5_prime_UTR	Exon 1 of 14	NP_001158009.1
	DISC1	NM_001012957.2		c.-38C>A		5_prime_UTR	Exon 1 of 13	NP_001012975.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	ENST00000439617.8	TSL:5 MANE Select	c.-38C>A		5_prime_UTR	Exon 1 of 13	ENSP00000403888.4
	DISC1	ENST00000366637.8	TSL:5	c.-38C>A		5_prime_UTR	Exon 1 of 13	ENSP00000355597.6
	DISC1	ENST00000366633.7	TSL:1	c.-38C>A		5_prime_UTR	Exon 1 of 10	ENSP00000355593.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.93e-7 AC: 1 AN: 1260558 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 618254

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24302

American (AMR) AF: 0.00 AC: 0 AN: 16640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18222

East Asian (EAS) AF: 0.00 AC: 0 AN: 31206

South Asian (SAS) AF: 0.00 AC: 0 AN: 61940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3558

European-Non Finnish (NFE) AF: 9.78e-7 AC: 1 AN: 1022106

Other (OTH) AF: 0.00 AC: 0 AN: 52148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.4
DANN	Benign	0.62
PhyloP100		0.16
PromoterAI		0.17	Neutral

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

Other links and lift over

hg19: chr1-231762576;