1-85464756-C-T

Position:

• chr1-85464756-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012137.4(DDAH1):​c.290G>A​(p.Ser97Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,164 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DDAH1 NM_012137.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

Genes affected

DDAH1 (HGNC:2715): (dimethylarginine dimethylaminohydrolase 1) This gene belongs to the dimethylarginine dimethylaminohydrolase (DDAH) gene family. The encoded enzyme plays a role in nitric oxide generation by regulating cellular concentrations of methylarginines, which in turn inhibit nitric oxide synthase activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDAH1	NM_012137.4	c.290G>A	p.Ser97Asn	missense_variant	1/6	ENST00000284031.13	NP_036269.1
DDAH1	NM_001134445.2	c.-7+31410G>A		intron_variant			NP_001127917.1
DDAH1	XM_005270707.3	c.19-105909G>A		intron_variant			XP_005270764.1
DDAH1	XM_011541158.2	c.-87+31410G>A		intron_variant			XP_011539460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDAH1	ENST00000284031.13	c.290G>A	p.Ser97Asn	missense_variant	1/6	1	NM_012137.4	ENSP00000284031	P1
DDAH1	ENST00000426972.8	c.-7+31410G>A		intron_variant		1		ENSP00000411189

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398164 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 691858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.290G>A (p.S97N) alteration is located in exon 1 (coding exon 1) of the DDAH1 gene. This alteration results from a G to A substitution at nucleotide position 290, causing the serine (S) at amino acid position 97 to be replaced by an asparagine (N). 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	0.52
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Benign	0.093	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.20
MutPred		0.47		Loss of phosphorylation at S97 (P = 0.0126);
MVP		0.59
MPC		0.91
ClinPred		0.93	D
GERP RS		4.0
Varity_R		0.67
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs201370663; hg19: chr1-85930439;