NM_001875.5:c.3928-9_3928-8delTT

Variant names:

• chr2-210663103-GTT-G
• rs397703682
• NM_001875.5:c.3928-9_3928-8delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001875.5(CPS1):​c.3928-9_3928-8delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,222,630 control chromosomes in the GnomAD database, including 83 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (51 hom., cov: 0)
  • Exomes 𝑓: 0.0080 (32 hom.)
• Consequence: CPS1 NM_001875.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.12
• Publications: 4 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-210663103-GTT-G is Benign according to our data. Variant chr2-210663103-GTT-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 429199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.015 (2216/147656) while in subpopulation AFR AF = 0.0481 (1949/40484). AF 95% confidence interval is 0.0464. There are 51 homozygotes in GnomAd4. There are 1028 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	NM_001875.5	MANE Select	c.3928-9_3928-8delTT		splice_region intron	N/A	NP_001866.2
	CPS1	NM_001369256.1		c.3961-9_3961-8delTT		splice_region intron	N/A	NP_001356185.1
	CPS1	NM_001122633.3		c.3928-9_3928-8delTT		splice_region intron	N/A	NP_001116105.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.3928-19_3928-18delTT		intron	N/A	ENSP00000233072.5
	CPS1	ENST00000430249.7	TSL:1	c.3946-19_3946-18delTT		intron	N/A	ENSP00000402608.2
	CPS1	ENST00000451903.3	TSL:1	c.2575-19_2575-18delTT		intron	N/A	ENSP00000406136.2

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2215 AN: 147580 Hom.: 51 Cov.: 0

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00689

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000784

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.00111

Gnomad MID AF: 0.0130

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0158 AC: 2831 AN: 179012 AF XY: 0.0153

Gnomad AFR exome AF: 0.0729

Gnomad AMR exome AF: 0.00927

Gnomad ASJ exome AF: 0.00801

Gnomad EAS exome AF: 0.00933

Gnomad FIN exome AF: 0.00632

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00801 AC: 8614 AN: 1074974 Hom.: 32 AF XY: 0.00772 AC XY: 4146 AN XY: 536896

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0656 AC: 1761 AN: 26850

American (AMR) AF: 0.00972 AC: 331 AN: 34066

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 81 AN: 19612

East Asian (EAS) AF: 0.00424 AC: 120 AN: 28312

South Asian (SAS) AF: 0.0118 AC: 779 AN: 66170

European-Finnish (FIN) AF: 0.00674 AC: 254 AN: 37664

Middle Eastern (MID) AF: 0.0111 AC: 52 AN: 4668

European-Non Finnish (NFE) AF: 0.00586 AC: 4764 AN: 813198

Other (OTH) AF: 0.0106 AC: 472 AN: 44434

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0150 AC: 2216 AN: 147656 Hom.: 51 Cov.: 0 AF XY: 0.0143 AC XY: 1028 AN XY: 71860

African (AFR) AF: 0.0481 AC: 1949 AN: 40484

American (AMR) AF: 0.00688 AC: 102 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.000786 AC: 4 AN: 5086

South Asian (SAS) AF: 0.00748 AC: 35 AN: 4680

European-Finnish (FIN) AF: 0.00111 AC: 10 AN: 9002

Middle Eastern (MID) AF: 0.0140 AC: 4 AN: 286

European-Non Finnish (NFE) AF: 0.00124 AC: 83 AN: 66896

Other (OTH) AF: 0.0142 AC: 29 AN: 2048

Alfa AF: 0.0285 Hom.: 2879

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Congenital hyperammonemia, type I Benign:2

May 18, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jan 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs397703682; hg19: chr2-211527827;