NM_004341.5:c.1843-1G>A

Variant names:

• chr2-27226130-G-A
• rs769567624
• NM_004341.5:c.1843-1G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004341.5(CAD):​c.1843-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAD NM_004341.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.68

Genes affected

CAD (HGNC:1424): (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. This gene encodes a trifunctional protein which is associated with the enzymatic activities of the first 3 enzymes in the 6-step pathway of pyrimidine biosynthesis: carbamoylphosphate synthetase (CPS II), aspartate transcarbamoylase, and dihydroorotase. This protein is regulated by the mitogen-activated protein kinase (MAPK) cascade, which indicates a direct link between activation of the MAPK cascade and de novo biosynthesis of pyrimidine nucleotides. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.028301887 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of -27, new splice context is: ctcctgactctgcttggcAGtga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-27226130-G-A is Pathogenic according to our data. Variant chr2-27226130-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 203465.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAD	NM_004341.5	c.1843-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 43	ENST00000264705.9	NP_004332.2
CAD	NM_001306079.2	c.1842+204G>A		intron_variant	Intron 12 of 42		NP_001293008.1
CAD	XM_047445803.1	c.1843-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 44		XP_047301759.1
CAD	XM_006712101.4	c.1842+204G>A		intron_variant	Intron 12 of 43		XP_006712164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAD	ENST00000264705.9	c.1843-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 43	1	NM_004341.5	ENSP00000264705.3
CAD	ENST00000403525.5	c.1842+204G>A		intron_variant	Intron 12 of 42	1		ENSP00000384510.1
CAD	ENST00000491891.1	n.-94G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251004 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461566 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727080

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 50 Pathogenic:1

Jun 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 12 of the CAD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CAD are known to be pathogenic (PMID: 28007989, 32117025, 32820246, 33497533). This variant is present in population databases (rs769567624, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with CAD-related conditions (PMID: 25678555). ClinVar contains an entry for this variant (Variation ID: 203465). Studies have shown that disruption of this splice site alters CAD gene expression (PMID: 25678555). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -26
DS_AL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs769567624; hg19: chr2-27448998;