rs3213784

Variant names:

• chr2-210650334-A-T
• rs3213784
• NM_001875.5:c.3405-29A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-210650334-A-T
• chr2-210650334-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001875.5(CPS1):​c.3405-29A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,580,844 control chromosomes in the GnomAD database, including 133,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.38 (11787 hom., cov: 32)
  • Exomes 𝑓: 0.41 (121790 hom.)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 2.81
• Publications: 14 publications found

Genes affected

CPS1 (HGNC:2323): (carbamoyl-phosphate synthase 1) The mitochondrial enzyme encoded by this gene catalyzes synthesis of carbamoyl phosphate from ammonia and bicarbonate. This reaction is the first committed step of the urea cycle, which is important in the removal of excess urea from cells. The encoded protein may also represent a core mitochondrial nucleoid protein. Three transcript variants encoding different isoforms have been found for this gene. The shortest isoform may not be localized to the mitochondrion. Mutations in this gene have been associated with carbamoyl phosphate synthetase deficiency, susceptibility to persistent pulmonary hypertension, and susceptibility to venoocclusive disease after bone marrow transplantation.[provided by RefSeq, May 2010]

CPS1 Gene-Disease associations (from GenCC):

• carbamoyl phosphate synthetase I deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-210650334-A-T is Benign according to our data. Variant chr2-210650334-A-T is described in ClinVar as Benign. ClinVar VariationId is 258479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001875.5. 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
	CPS1	NM_001875.5	MANE Select	c.3405-29A>T		intron	N/A	NP_001866.2
	CPS1	NM_001369256.1		c.3438-29A>T		intron	N/A	NP_001356185.1
	CPS1	NM_001122633.3		c.3405-29A>T		intron	N/A	NP_001116105.2	P31327-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.3405-29A>T		intron	N/A	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.3423-29A>T		intron	N/A	ENSP00000402608.2	P31327-3
	CPS1	ENST00000451903.3	TSL:1	c.2052-29A>T		intron	N/A	ENSP00000406136.2	P31327-2

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58362 AN: 151796 Hom.: 11785 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.397

GnomAD2 exomes AF: 0.425 AC: 106621 AN: 250998 AF XY: 0.423

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.503

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.520

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.410 AC: 585457 AN: 1428928 Hom.: 121790 Cov.: 27 AF XY: 0.408 AC XY: 291302 AN XY: 713138

African (AFR) AF: 0.263 AC: 8635 AN: 32798

American (AMR) AF: 0.502 AC: 22378 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 8821 AN: 25920

East Asian (EAS) AF: 0.499 AC: 19695 AN: 39496

South Asian (SAS) AF: 0.414 AC: 35452 AN: 85570

European-Finnish (FIN) AF: 0.479 AC: 25529 AN: 53352

Middle Eastern (MID) AF: 0.289 AC: 1650 AN: 5712

European-Non Finnish (NFE) AF: 0.406 AC: 439527 AN: 1082278

Other (OTH) AF: 0.401 AC: 23770 AN: 59208

GnomAD4 genome AF: 0.384 AC: 58395 AN: 151916 Hom.: 11787 Cov.: 32 AF XY: 0.389 AC XY: 28906 AN XY: 74262

African (AFR) AF: 0.270 AC: 11186 AN: 41458

American (AMR) AF: 0.467 AC: 7125 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1153 AN: 3464

East Asian (EAS) AF: 0.521 AC: 2679 AN: 5144

South Asian (SAS) AF: 0.421 AC: 2027 AN: 4814

European-Finnish (FIN) AF: 0.481 AC: 5082 AN: 10556

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27916 AN: 67908

Other (OTH) AF: 0.395 AC: 834 AN: 2110

Alfa AF: 0.387 Hom.: 2126

Bravo AF: 0.378

Asia WGS AF: 0.456 AC: 1584 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Congenital hyperammonemia, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	17
DANN	Benign	0.60
PhyloP100		2.8
La Branchor		0.84
BranchPoint Hunter		5.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3213784; hg19: chr2-211515058; COSMIC: COSV51811843; COSMIC: COSV51811843;