Genetic Variant DDAH2:p.Thr155Met (chr6-31728458-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001303007.2(DDAH2):c.464C>T(p.Thr155Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,612,402 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

DDAH2
NM_001303007.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.58

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDAH2	NM_001303007.2 link	c.464C>T	p.Thr155Met	missense_variant	Exon 3 of 6	ENST00000375789.7	NP_001289936.1	O95865V9HW53
DDAH2	NM_001303008.2 link	c.464C>T	p.Thr155Met	missense_variant	Exon 4 of 7		NP_001289937.1	O95865V9HW53
DDAH2	NM_013974.3 link	c.464C>T	p.Thr155Met	missense_variant	Exon 4 of 7		NP_039268.1	O95865V9HW53
DDAH2	XM_011514448.3 link	c.464C>T	p.Thr155Met	missense_variant	Exon 4 of 7		XP_011512750.1	O95865V9HW53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDAH2	ENST00000375789.7 link	c.464C>T	p.Thr155Met	missense_variant	Exon 3 of 6	2	NM_001303007.2	ENSP00000364945.2		O95865

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000150

AC:

AN:

245920

AF XY:

0.000208

show subpopulations

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:

0.0000925

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000284

AC:

415

AN:

1460572

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

214

AN XY:

726600

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.000202

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000134

AC:

AN:

52246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.000347

AC:

386

AN:

1111970

Other (OTH)

AF:

0.000199

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000191

AC:

AN:

151830

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74186

show subpopulations

African (AFR)

AF:

0.0000726

AC:

AN:

41318

American (AMR)

AF:

0.0000656

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

67940

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000458

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.000332

AC:

ESP6500EA

AF:

0.000185

AC:

ExAC

AF:

0.000154

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.464C>T (p.T155M) alteration is located in exon 4 (coding exon 3) of the DDAH2 gene. This alteration results from a C to T substitution at nucleotide position 464, causing the threonine (T) at amino acid position 155 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;T;T;T;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.71

D;D;D;D;D

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.0

M;M;M;.;.

PhyloP100

8.6

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.0

D;D;D;D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;.;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.49

MVP

0.38

MPC

2.1

ClinPred

0.76

GERP RS

5.4

PromoterAI

0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.83

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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6-31728458-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over