X-120526797-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001079872.2(CUL4B):ā€‹c.2652T>Gā€‹(p.Asp884Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,035 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 23)
Exomes š‘“: 0.0000018 ( 0 hom. 1 hem. )

Consequence

CUL4B
NM_001079872.2 missense

Scores

4
12
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.58
Variant links:
Genes affected
CUL4B (HGNC:2555): (cullin 4B) This gene is a member of the cullin family. The encoded protein forms a complex that functions as an E3 ubiquitin ligase and catalyzes the polyubiquitination of specific protein substrates in the cell. The protein interacts with a ring finger protein, and is required for the proteolysis of several regulators of DNA replication including chromatin licensing and DNA replication factor 1 and cyclin E. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CUL4BNM_001079872.2 linkc.2652T>G p.Asp884Glu missense_variant Exon 20 of 20 ENST00000371322.11 NP_001073341.1 Q13620-1
CUL4BNM_003588.4 linkc.2706T>G p.Asp902Glu missense_variant Exon 22 of 22 NP_003579.3 Q13620-2
CUL4BNM_001330624.2 linkc.2667T>G p.Asp889Glu missense_variant Exon 21 of 21 NP_001317553.1 K4DI93
CUL4BNM_001369145.1 linkc.2118T>G p.Asp706Glu missense_variant Exon 20 of 20 NP_001356074.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CUL4BENST00000371322.11 linkc.2652T>G p.Asp884Glu missense_variant Exon 20 of 20 1 NM_001079872.2 ENSP00000360373.5 Q13620-1
CUL4BENST00000681206.1 linkc.2766T>G p.Asp922Glu missense_variant Exon 23 of 23 ENSP00000505480.1 A0A7P0T954
CUL4BENST00000680673.1 linkc.2706T>G p.Asp902Glu missense_variant Exon 22 of 22 ENSP00000505084.1 Q13620-2
CUL4BENST00000681253.1 linkc.2706T>G p.Asp902Glu missense_variant Exon 23 of 23 ENSP00000506259.1 Q13620-2
CUL4BENST00000681652.1 linkc.2706T>G p.Asp902Glu missense_variant Exon 25 of 25 ENSP00000505176.1 Q13620-2
CUL4BENST00000336592.11 linkc.2667T>G p.Asp889Glu missense_variant Exon 21 of 21 5 ENSP00000338919.6 K4DI93
CUL4BENST00000674137.11 linkc.2658T>G p.Asp886Glu missense_variant Exon 20 of 20 ENSP00000501019.6 A0A669KAX4
CUL4BENST00000681090.1 linkc.2559T>G p.Asp853Glu missense_variant Exon 20 of 20 ENSP00000506288.1 A0A7P0TAQ3
CUL4BENST00000404115.8 linkc.2499T>G p.Asp833Glu missense_variant Exon 19 of 19 1 ENSP00000384109.4 A0A804CL36
CUL4BENST00000679927.1 linkc.2307T>G p.Asp769Glu missense_variant Exon 21 of 21 ENSP00000505603.1 A0A7P0T9L3
CUL4BENST00000371323.3 linkc.2118T>G p.Asp706Glu missense_variant Exon 20 of 20 5 ENSP00000360374.3 Q13620-3
CUL4BENST00000679844.1 linkc.1989T>G p.Asp663Glu missense_variant Exon 18 of 18 ENSP00000505239.1 A0A7P0T8P8
CUL4BENST00000680474 linkc.*98T>G 3_prime_UTR_variant Exon 20 of 20 ENSP00000505562.1 A0A7P0T9C8
CUL4BENST00000673919.1 linkn.*2099T>G non_coding_transcript_exon_variant Exon 21 of 21 ENSP00000500994.1 A0A669KAU9
CUL4BENST00000674073.2 linkn.*208T>G non_coding_transcript_exon_variant Exon 18 of 18 ENSP00000501262.2 A0A669KBG9
CUL4BENST00000679405.1 linkn.*1861T>G non_coding_transcript_exon_variant Exon 22 of 22 ENSP00000504985.1 A0A7P0Z439
CUL4BENST00000679432.1 linkn.*1861T>G non_coding_transcript_exon_variant Exon 22 of 22 ENSP00000505343.1 A0A7P0T8W4
CUL4BENST00000680918.1 linkn.*1568T>G non_coding_transcript_exon_variant Exon 18 of 18 ENSP00000505955.1 A0A7P0Z4G9
CUL4BENST00000681080.1 linkn.*1861T>G non_coding_transcript_exon_variant Exon 20 of 20 ENSP00000505898.1 A0A7P0Z4E4
CUL4BENST00000681189.1 linkn.*818T>G non_coding_transcript_exon_variant Exon 20 of 20 ENSP00000505973.1 A0A7P0TAF9
CUL4BENST00000681333.1 linkn.*3545T>G non_coding_transcript_exon_variant Exon 17 of 17 ENSP00000505739.1 A0A7P0T9R8
CUL4BENST00000681908.1 linkn.*824T>G non_coding_transcript_exon_variant Exon 20 of 20 ENSP00000505777.1 A0A7P0T9P5
CUL4BENST00000673919.1 linkn.*2099T>G 3_prime_UTR_variant Exon 21 of 21 ENSP00000500994.1 A0A669KAU9
CUL4BENST00000674073.2 linkn.*208T>G 3_prime_UTR_variant Exon 18 of 18 ENSP00000501262.2 A0A669KBG9
CUL4BENST00000679405.1 linkn.*1861T>G 3_prime_UTR_variant Exon 22 of 22 ENSP00000504985.1 A0A7P0Z439
CUL4BENST00000679432.1 linkn.*1861T>G 3_prime_UTR_variant Exon 22 of 22 ENSP00000505343.1 A0A7P0T8W4
CUL4BENST00000680918.1 linkn.*1568T>G 3_prime_UTR_variant Exon 18 of 18 ENSP00000505955.1 A0A7P0Z4G9
CUL4BENST00000681080.1 linkn.*1861T>G 3_prime_UTR_variant Exon 20 of 20 ENSP00000505898.1 A0A7P0Z4E4
CUL4BENST00000681189.1 linkn.*818T>G 3_prime_UTR_variant Exon 20 of 20 ENSP00000505973.1 A0A7P0TAF9
CUL4BENST00000681333.1 linkn.*3545T>G 3_prime_UTR_variant Exon 17 of 17 ENSP00000505739.1 A0A7P0T9R8
CUL4BENST00000681908.1 linkn.*824T>G 3_prime_UTR_variant Exon 20 of 20 ENSP00000505777.1 A0A7P0T9P5

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.0000109
AC:
2
AN:
183050
Hom.:
0
AF XY:
0.0000148
AC XY:
1
AN XY:
67578
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000729
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000184
AC:
2
AN:
1084035
Hom.:
0
Cov.:
26
AF XY:
0.00000285
AC XY:
1
AN XY:
351197
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000573
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

X-linked intellectual disability Cabezas type Uncertain:1
Feb 03, 2021
Breda Genetics srl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, and/or variant type outside the known gene mutational spectrum. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Uncertain
0.064
T
BayesDel_noAF
Uncertain
0.040
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
.;.;D
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Pathogenic
0.76
D;D;D
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Uncertain
2.5
.;.;M
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.5
D;D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.019
D;D;D
Sift4G
Uncertain
0.055
T;T;T
Polyphen
1.0
D;.;D
Vest4
0.68
MutPred
0.63
.;.;Gain of glycosylation at P906 (P = 0.1344);
MVP
0.95
MPC
1.7
ClinPred
0.53
D
GERP RS
0.56
Varity_R
0.75
gMVP
0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs768424127; hg19: chrX-119660652; API