7-148730226-A-C

Position:

• chr7-148730226-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003592.3(CUL1):​c.104A>C​(p.Gln35Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUL1 NM_003592.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.88

Genes affected

CUL1 (HGNC:2551): (cullin 1) Predicted to enable ubiquitin protein ligase binding activity and ubiquitin-protein transferase activity. Involved in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process and protein ubiquitination. Located in plasma membrane. Part of Parkin-FBXW7-Cul1 ubiquitin ligase complex and SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

CUL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL1	NM_003592.3	c.104A>C	p.Gln35Pro	missense_variant	2/22	ENST00000325222.9	NP_003583.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL1	ENST00000325222.9	c.104A>C	p.Gln35Pro	missense_variant	2/22	1	NM_003592.3	ENSP00000326804.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2024

The c.104A>C (p.Q35P) alteration is located in exon 2 (coding exon 1) of the CUL1 gene. This alteration results from a A to C substitution at nucleotide position 104, causing the glutamine (Q) at amino acid position 35 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T;T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;L;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D;.;D;.
REVEL	Benign	0.25
Sift	Benign	0.032	D;.;D;.
Sift4G	Benign	0.074	T;T;T;T
Polyphen		0.99	D;D;D;.
Vest4		0.69
MutPred		0.53		Gain of glycosylation at Q35 (P = 0.0234);Gain of glycosylation at Q35 (P = 0.0234);Gain of glycosylation at Q35 (P = 0.0234);Gain of glycosylation at Q35 (P = 0.0234);
MVP		0.56
MPC		2.6
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.89
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-148427318;