chr6-31728911-T-A

Variant names:

• chr6-31728911-T-A
• NM_001303007.2:c.251A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001303007.2(DDAH2):​c.251A>T​(p.Asp84Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDAH2 NM_001303007.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDAH2	NM_001303007.2	c.251A>T	p.Asp84Val	missense_variant	Exon 1 of 6	ENST00000375789.7	NP_001289936.1
DDAH2	NM_001303008.2	c.251A>T	p.Asp84Val	missense_variant	Exon 2 of 7		NP_001289937.1
DDAH2	NM_013974.3	c.251A>T	p.Asp84Val	missense_variant	Exon 2 of 7		NP_039268.1
DDAH2	XM_011514448.3	c.251A>T	p.Asp84Val	missense_variant	Exon 2 of 7		XP_011512750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDAH2	ENST00000375789.7	c.251A>T	p.Asp84Val	missense_variant	Exon 1 of 6	2	NM_001303007.2	ENSP00000364945.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.251A>T (p.D84V) alteration is located in exon 2 (coding exon 1) of the DDAH2 gene. This alteration results from a A to T substitution at nucleotide position 251, causing the aspartic acid (D) at amino acid position 84 to be replaced by a valine (V). 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	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.6	M;M;M;.;.
PhyloP100		4.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0080	D;D;D;D;D
Sift4G	Uncertain	0.043	D;D;D;.;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.69
MutPred		0.67		Loss of disorder (P = 0.0534);Loss of disorder (P = 0.0534);Loss of disorder (P = 0.0534);Loss of disorder (P = 0.0534);Loss of disorder (P = 0.0534);
MVP		0.41
MPC		2.4
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.96
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr6-31696688;