dbSNP rs149444280: DISC1:p.Val71Met (chr1-231693969-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018662.3(DISC1):c.211G>A(p.Val71Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,758 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V71L) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DISC1
NM_018662.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.544

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 made for transcript

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=0.05345133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3 link	c.211G>A	p.Val71Met	missense_variant	Exon 2 of 13	ENST00000439617.8	NP_061132.2	Q9NRI5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DISC1	ENST00000439617.8 link	c.211G>A	p.Val71Met	missense_variant	Exon 2 of 13	5	NM_018662.3	ENSP00000403888.4	Q9NRI5-1
DISC1	ENST00000366637.8 link	c.211G>A	p.Val71Met	missense_variant	Exon 2 of 13	5		ENSP00000355597.6	Q9NRI5-2
TSNAX-DISC1	ENST00000602956.5 link	n.*72G>A		non_coding_transcript_exon_variant	Exon 6 of 13	2		ENSP00000473532.1	C4P0D8
TSNAX-DISC1	ENST00000602956.5 link	n.*72G>A		3_prime_UTR_variant	Exon 6 of 13	2		ENSP00000473532.1	C4P0D8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727168

show subpopulations

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

6.4

DANN

Benign

0.88

DEOGEN2

Benign

0.0094

.;.;.;.;.;.;.;.;.;T;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.74

T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.053

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;L;L;.;L;L;L;L;.;.;L;L

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.74

N;N;.;N;N;N;.;N;N;.;.;N;.

REVEL

Benign

0.024

Sift

Benign

0.18

T;T;.;.;T;T;.;T;T;.;.;T;.

Sift4G

Benign

0.22

T;T;T;T;T;T;T;T;T;T;T;T;.

Polyphen

0.0010

B;.;.;.;B;B;.;.;B;.;.;B;.

Vest4

0.16

MutPred

0.12

Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);Loss of catalytic residue at V71 (P = 0.0116);

MVP

0.16

MPC

0.14

ClinPred

0.17

GERP RS

-0.44

Varity_R

0.022

gMVP

0.10

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over