NM_003590.5:c.1207-3C>T

Variant names:

• chr2-224503825-G-A
• rs199469653
• NM_003590.5:c.1207-3C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_003590.5(CUL3):​c.1207-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CUL3 NM_003590.5 splice_region, intron
• Scores: Splicing: ADA: 0.2380
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.27
• Publications: 4 publications found

Genes affected

CUL3 (HGNC:2553): (cullin 3) This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation. Mutations in this gene are a cause of type 2E pseudohypoaldosteronism. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

CUL3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without autism or seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• pseudohypoaldosteronism type 2E

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-224503825-G-A is Pathogenic according to our data. Variant chr2-224503825-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 100519.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003590.5. 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
	CUL3	NM_003590.5	MANE Select	c.1207-3C>T		splice_region intron	N/A	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.1225-3C>T		splice_region intron	N/A	NP_001244127.1
	CUL3	NM_001257197.2		c.1009-3C>T		splice_region intron	N/A	NP_001244126.1	Q13618-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL3	ENST00000264414.9	TSL:1 MANE Select	c.1207-3C>T		splice_region intron	N/A	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000409096.5	TSL:1	c.1135-3C>T		splice_region intron	N/A	ENSP00000387200.1	Q13618-2
	CUL3	ENST00000409777.5	TSL:1	c.1135-3C>T		splice_region intron	N/A	ENSP00000386525.1	Q13618-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.25e-7 AC: 1 AN: 1379776 Hom.: 0 Cov.: 29 AF XY: 0.00000147 AC XY: 1 AN XY: 681984

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

African (AFR) AF: 0.00 AC: 0 AN: 30502

American (AMR) AF: 0.0000344 AC: 1 AN: 29112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22218

East Asian (EAS) AF: 0.00 AC: 0 AN: 38278

South Asian (SAS) AF: 0.00 AC: 0 AN: 73104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5392

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074058

Other (OTH) AF: 0.00 AC: 0 AN: 56754

⚠️ 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 Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pseudohypoaldosteronism type 2A (1)
1	-	-	Pseudohypoaldosteronism type 2E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.94
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.24
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -3

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

Other links and lift over

dbSNP: rs199469653; hg19: chr2-225368542;