Genetic Variant DDAH2:p.Pro4Gln (chr6-31729151-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001303007.2(DDAH2):c.11C>A(p.Pro4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. P4R) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DDAH2
NM_001303007.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.04

Publications

0 publications found

Variant links:

Genes affected

DDAH2 (HGNC:2716): (DDAH family member 2, ADMA-independent) This gene encodes a dimethylarginine dimethylaminohydrolase. The encoded enzyme functions in nitric oxide generation by regulating the cellular concentrations of methylarginines, which in turn inhibit nitric oxide synthase activity. The protein may be localized to the mitochondria. Alternative splicing resulting in multiple transcript variants. [provided by RefSeq, Dec 2014]

DDAH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2320565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDAH2	NM_001303007.2 link	c.11C>A	p.Pro4Gln	missense_variant	Exon 1 of 6	ENST00000375789.7	NP_001289936.1	O95865V9HW53
DDAH2	NM_001303008.2 link	c.11C>A	p.Pro4Gln	missense_variant	Exon 2 of 7		NP_001289937.1	O95865V9HW53
DDAH2	NM_013974.3 link	c.11C>A	p.Pro4Gln	missense_variant	Exon 2 of 7		NP_039268.1	O95865V9HW53
DDAH2	XM_011514448.3 link	c.11C>A	p.Pro4Gln	missense_variant	Exon 2 of 7		XP_011512750.1	O95865V9HW53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDAH2	ENST00000375789.7 link	c.11C>A	p.Pro4Gln	missense_variant	Exon 1 of 6	2	NM_001303007.2	ENSP00000364945.2		O95865

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1454494

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722852

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.00

AC:

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25846

East Asian (EAS)

AF:

0.00

AC:

AN:

39558

South Asian (SAS)

AF:

0.00

AC:

AN:

86006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1107404

Other (OTH)

AF:

0.00

AC:

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0085

T;T;T;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.88

M_CAP

Benign

0.0084

MetaRNN

Benign

0.23

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;L;.;.

PhyloP100

3.0

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.16

N;N;N;N;N

REVEL

Benign

0.10

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Benign

0.13

T;T;T;.;T

Polyphen

0.99

D;D;D;.;.

Vest4

0.31

MutPred

0.23

Loss of phosphorylation at T3 (P = 0.0533);Loss of phosphorylation at T3 (P = 0.0533);Loss of phosphorylation at T3 (P = 0.0533);Loss of phosphorylation at T3 (P = 0.0533);Loss of phosphorylation at T3 (P = 0.0533);

MVP

0.10

MPC

0.90

ClinPred

0.90

GERP RS

5.1

PromoterAI

0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.16

gMVP

0.35

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over