1-85324859-G-T

Variant names:

• chr1-85324859-G-T
• rs377746010
• NM_012137.4:c.622C>A

Variant summary

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

The NM_012137.4(DDAH1):​c.622C>A​(p.Arg208Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R208G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DDAH1 NM_012137.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.14
• Publications: 1 publications found

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]

BCL10-AS1 (HGNC:55868): (BCL10 antisense RNA 1)

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012137.4. 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
	DDAH1	NM_012137.4	MANE Select	c.622C>A	p.Arg208Ser	missense	Exon 5 of 6	NP_036269.1	B2R644
	DDAH1	NM_001330655.2		c.322C>A	p.Arg108Ser	missense	Exon 5 of 6	NP_001317584.1	B4DYP1
	DDAH1	NM_001134445.2		c.313C>A	p.Arg105Ser	missense	Exon 6 of 7	NP_001127917.1	O94760-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDAH1	ENST00000284031.13	TSL:1 MANE Select	c.622C>A	p.Arg208Ser	missense	Exon 5 of 6	ENSP00000284031.8	O94760-1
	DDAH1	ENST00000426972.8	TSL:1	c.313C>A	p.Arg105Ser	missense	Exon 6 of 7	ENSP00000411189.4	O94760-2
	DDAH1	ENST00000866624.1		c.502C>A	p.Arg168Ser	missense	Exon 4 of 5	ENSP00000536683.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.68	N
PhyloP100		5.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Sift4G	Benign	0.57	T
Polyphen		0.012	B
Vest4		0.84
MutPred		0.43		Loss of catalytic residue at R208 (P = 0.0064)
MVP		0.41
MPC		0.39
ClinPred		0.72	D
GERP RS		5.9
Varity_R		0.75
gMVP		0.72
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs377746010; hg19: chr1-85790542;