DISC1 p.Leu607Phe

Variant names:

• chr1-231818355-C-T
• rs6675281
• NM_018662.3:c.1819C>T
• DISC1 p.Leu607Phe

Your query was ambiguous. Multiple possible variants found:

• chr1-231818355-C-T
• chr1-231818355-CTC-TTT

GermlineCancer (beta)

Variant summary

Our verdict is

Benign

-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received -10 classification points (ACMG Germline Pathogenicity v2019): 0P and 10B. BA1BP4_Moderate

The NM_018662.3(DISC1):c.1819C>T (p.Leu607Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.13 (AC=210,366) in the gnomAD database across 1,613,712 control chromosomes, including 15,127 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.177. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.14 (1709 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13418 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.36
• Publications: 95 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]

ENSG00000286071 (HGNC:):

DISC2 (HGNC:2889): (disrupted in schizophrenia 2) DISC2 is thought to specify a noncoding RNA molecule antisense to DISC1 (MIM 605210). Both genes were found to be disrupted by a translocation in a large schizophrenia (MIM 181500) kindred.[supplied by OMIM, Jul 2002]

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -10 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1771 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_018662.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	NM_018662.3	MANE Select	c.1819C>T	p.Leu607Phe	missense	Exon 9 of 13	NP_061132.2	Q9NRI5-1
	DISC1	NM_001164537.2		c.1915C>T	p.Leu639Phe	missense	Exon 10 of 14	NP_001158009.1	C4P096
	DISC1	NM_001012957.2		c.1819C>T	p.Leu607Phe	missense	Exon 9 of 13	NP_001012975.1	Q9NRI5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISC1	ENST00000439617.8	TSL:5 MANE Select	c.1819C>T	p.Leu607Phe	missense	Exon 9 of 13	ENSP00000403888.4	Q9NRI5-1
	DISC1	ENST00000366637.8	TSL:5	c.1819C>T	p.Leu607Phe	missense	Exon 9 of 13	ENSP00000355597.6	Q9NRI5-2
	DISC1	ENST00000366633.7	TSL:1	c.1819C>T	p.Leu607Phe	missense	Exon 9 of 10	ENSP00000355593.3	Q9NRI5-5

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21126 AN: 152032 Hom.: 1702 Cov.: 33

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.0811

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.111 AC: 27823 AN: 251170 AF XY: 0.110

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.0537

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.00310

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.129 AC: 189219 AN: 1461562 Hom.: 13418 Cov.: 31 AF XY: 0.127 AC XY: 92445 AN XY: 727090

African (AFR) AF: 0.181 AC: 6054 AN: 33466

American (AMR) AF: 0.0577 AC: 2582 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2672 AN: 26128

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39698

South Asian (SAS) AF: 0.0565 AC: 4869 AN: 86248

European-Finnish (FIN) AF: 0.150 AC: 7988 AN: 53416

Middle Eastern (MID) AF: 0.0901 AC: 518 AN: 5752

European-Non Finnish (NFE) AF: 0.141 AC: 157118 AN: 1111768

Other (OTH) AF: 0.122 AC: 7351 AN: 60376

GnomAD4 genome AF: 0.139 AC: 21147 AN: 152150 Hom.: 1709 Cov.: 33 AF XY: 0.135 AC XY: 10077 AN XY: 74374

African (AFR) AF: 0.180 AC: 7471 AN: 41492

American (AMR) AF: 0.0810 AC: 1239 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 406 AN: 3468

East Asian (EAS) AF: 0.00425 AC: 22 AN: 5174

South Asian (SAS) AF: 0.0483 AC: 233 AN: 4822

European-Finnish (FIN) AF: 0.151 AC: 1599 AN: 10584

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9661 AN: 67998

Other (OTH) AF: 0.124 AC: 262 AN: 2114

Alfa AF: 0.135 Hom.: 4984

Bravo AF: 0.137

Asia WGS AF: 0.0460 AC: 164 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.129

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.000244 AC: 30 AN: 122758

Turkish Variome AF: 0.101 AC: 655 AN: 6492 Hom.: 47

WBBC (Westlake BioBank for Chinese) pilot AF: 0.00379 AC: 34 AN: 8960 Hom.: 1

ABraOM SABE-WGS-1171 AF: 0.124 AC: 290 AN: 2342 Hom.: 22

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Varity_R		0.099
gMVP		0.30
Mutation Taster		=296/4	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6675281;

hg19: chr1-231954101;

COSMIC: COSV54404138;

COSMIC: COSV54404138;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar