Genetic Variant DAOA:p.Arg122Leu (chr13-105489984-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_172370.5(DAOA):c.365G>T(p.Arg122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R122C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

DAOA
NM_172370.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.515

Publications

2 publications found

Variant links:

Genes affected

DAOA (HGNC:21191): (D-amino acid oxidase activator) This gene encodes a protein that may function as an activator of D-amino acid oxidase, which degrades the gliotransmitter D-serine, a potent activator of N-methyl-D-aspartate (NMDA) type glutamate receptors. Studies also suggest that one encoded isoform may play a role in mitochondrial function and dendritic arborization. Polymorphisms in this gene have been implicated in susceptibility to schizophrenia and bipolar affective disorder. Alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Mar 2011]

DAOA links:

DAOA-AS1 (HGNC:30243): (DAOA antisense RNA 1)

DAOA-AS1 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 (MetaRNN=0.04956627).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172370.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DAOA	NM_172370.5	MANE Select	c.365G>T	p.Arg122Leu	missense	Exon 5 of 6	NP_758958.3
DAOA	NM_001161812.1		c.281G>T	p.Arg94Leu	missense	Exon 4 of 5	NP_001155284.1	A2T115
DAOA	NM_001384645.1		c.158G>T	p.Arg53Leu	missense	Exon 6 of 7	NP_001371574.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DAOA	ENST00000375936.9	TSL:1 MANE Select	c.365G>T	p.Arg122Leu	missense	Exon 5 of 6	ENSP00000365103.3	P59103-1
DAOA	ENST00000595812.2	TSL:1	c.281G>T	p.Arg94Leu	missense	Exon 4 of 5	ENSP00000469539.1	A2T115
DAOA	ENST00000329625.9	TSL:1	c.152G>T	p.Arg51Leu	missense	Exon 4 of 4	ENSP00000329951.5	P59103-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

244678

AF XY:

0.00

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:

0.00000616

AC:

AN:

1460988

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726796

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111716

Other (OTH)

AF:

0.00

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.24

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.031

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.36

M_CAP

Benign

0.0018

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.52

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.2

REVEL

Benign

0.027

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.12

MutPred

0.29

Gain of catalytic residue at K120 (P = 0.001)

MVP

0.14

MPC

0.0039

ClinPred

0.046

GERP RS

-2.9

Varity_R

0.13

gMVP

0.0099

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over