13-105467143-T-C

Variant names:

• chr13-105467143-T-C
• rs148297571
• NM_172370.5:c.133+2T>C

Variant summary

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

The NM_172370.5(DAOA):​c.133+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DAOA NM_172370.5 splice_donor, intron
• Scores: Splicing: ADA: 0.7299
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.915
• Publications: 0 publications found

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

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_addAF=-0.450822).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAOA	NM_172370.5	MANE Select	c.133+2T>C		splice_donor intron	N/A	NP_758958.3
	DAOA	NM_001384644.1		c.133+2T>C		splice_donor intron	N/A	NP_001371573.1	P59103-4
	DAOA	NM_001161812.1		c.-61+2T>C		splice_donor intron	N/A	NP_001155284.1	A2T115

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAOA	ENST00000375936.9	TSL:1 MANE Select	c.133+2T>C		splice_donor intron	N/A	ENSP00000365103.3	P59103-1
	DAOA	ENST00000595812.2	TSL:1	c.-61+2T>C		splice_donor intron	N/A	ENSP00000469539.1	A2T115
	DAOA	ENST00000329625.9	TSL:1	c.-81+2T>C		splice_donor intron	N/A	ENSP00000329951.5	P59103-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450106 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721238

⚠️ 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: 33254

American (AMR) AF: 0.00 AC: 0 AN: 43574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39408

South Asian (SAS) AF: 0.00 AC: 0 AN: 84288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105672

Other (OTH) AF: 0.00 AC: 0 AN: 59936

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	16
DANN	Benign	0.72
Eigen	Benign	0.10
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.043	N
PhyloP100		0.92
GERP RS		0.61
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148297571; hg19: chr13-106119492;