11-108052759-G-A

Position:

• chr11-108052759-G-A

Variant summary

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

The ENST00000393094.7(CUL5):​c.511G>A​(p.Ala171Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CUL5 ENST00000393094.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96

Genes affected

CUL5 (HGNC:2556): (cullin 5) Enables ubiquitin protein ligase binding activity. Predicted to be involved in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process and protein ubiquitination. Predicted to act upstream of or within cerebral cortex radially oriented cell migration and radial glia guided migration of Purkinje cell. Located in site of DNA damage. Part of Cul5-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

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
CUL5	NM_003478.6	c.511G>A	p.Ala171Thr	missense_variant	5/19	ENST00000393094.7	NP_003469.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL5	ENST00000393094.7	c.511G>A	p.Ala171Thr	missense_variant	5/19	1	NM_003478.6	ENSP00000376808	P1
CUL5	ENST00000531427.5	c.511G>A	p.Ala171Thr	missense_variant, NMD_transcript_variant	5/20	1		ENSP00000435376
CUL5	ENST00000532782.1	c.202G>A	p.Ala68Thr	missense_variant	2/3	3		ENSP00000431221
CUL5	ENST00000532064.5	c.*267G>A		3_prime_UTR_variant, NMD_transcript_variant	4/6	5		ENSP00000436494

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

May 28, 2024

The c.511G>A (p.A171T) alteration is located in exon 5 (coding exon 5) of the CUL5 gene. This alteration results from a G to A substitution at nucleotide position 511, causing the alanine (A) at amino acid position 171 to be replaced by a threonine (T). 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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.37
Sift	Benign	0.29	T
Sift4G	Benign	0.25	T
Polyphen		0.93	P
Vest4		0.62
MutPred		0.67		Loss of catalytic residue at A171 (P = 0.2377);
MVP		0.75
MPC		1.4
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.24
gMVP		0.32

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-107923486;