X-120530127-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001079872.2(CUL4B):​c.2567A>T​(p.Tyr856Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,097,026 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

CUL4B
NM_001079872.2 missense

Scores

2
2
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.41170964).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CUL4BNM_001079872.2 linkc.2567A>T p.Tyr856Phe missense_variant Exon 19 of 20 ENST00000371322.11 NP_001073341.1 Q13620-1
CUL4BNM_003588.4 linkc.2621A>T p.Tyr874Phe missense_variant Exon 21 of 22 NP_003579.3 Q13620-2
CUL4BNM_001330624.2 linkc.2582A>T p.Tyr861Phe missense_variant Exon 20 of 21 NP_001317553.1 K4DI93
CUL4BNM_001369145.1 linkc.2033A>T p.Tyr678Phe missense_variant Exon 19 of 20 NP_001356074.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CUL4BENST00000371322.11 linkc.2567A>T p.Tyr856Phe missense_variant Exon 19 of 20 1 NM_001079872.2 ENSP00000360373.5 Q13620-1
CUL4BENST00000681206.1 linkc.2681A>T p.Tyr894Phe missense_variant Exon 22 of 23 ENSP00000505480.1 A0A7P0T954
CUL4BENST00000680673.1 linkc.2621A>T p.Tyr874Phe missense_variant Exon 21 of 22 ENSP00000505084.1 Q13620-2
CUL4BENST00000681253.1 linkc.2621A>T p.Tyr874Phe missense_variant Exon 22 of 23 ENSP00000506259.1 Q13620-2
CUL4BENST00000681652.1 linkc.2621A>T p.Tyr874Phe missense_variant Exon 24 of 25 ENSP00000505176.1 Q13620-2
CUL4BENST00000336592.11 linkc.2582A>T p.Tyr861Phe missense_variant Exon 20 of 21 5 ENSP00000338919.6 K4DI93
CUL4BENST00000674137.11 linkc.2573A>T p.Tyr858Phe missense_variant Exon 19 of 20 ENSP00000501019.6 A0A669KAX4
CUL4BENST00000681090.1 linkc.2474A>T p.Tyr825Phe missense_variant Exon 19 of 20 ENSP00000506288.1 A0A7P0TAQ3
CUL4BENST00000679927.1 linkc.2222A>T p.Tyr741Phe missense_variant Exon 20 of 21 ENSP00000505603.1 A0A7P0T9L3
CUL4BENST00000371323.3 linkc.2033A>T p.Tyr678Phe missense_variant Exon 19 of 20 5 ENSP00000360374.3 Q13620-3
CUL4BENST00000680474.1 linkc.2009A>T p.Tyr670Phe missense_variant Exon 18 of 20 ENSP00000505562.1 A0A7P0T9C8
CUL4BENST00000679844.1 linkc.1904A>T p.Tyr635Phe missense_variant Exon 17 of 18 ENSP00000505239.1 A0A7P0T8P8
CUL4BENST00000404115.8 linkc.2439+2295A>T intron_variant Intron 18 of 18 1 ENSP00000384109.4 A0A804CL36
CUL4BENST00000673919.1 linkn.*2014A>T non_coding_transcript_exon_variant Exon 20 of 21 ENSP00000500994.1 A0A669KAU9
CUL4BENST00000674073.2 linkn.*123A>T non_coding_transcript_exon_variant Exon 17 of 18 ENSP00000501262.2 A0A669KBG9
CUL4BENST00000679405.1 linkn.*1776A>T non_coding_transcript_exon_variant Exon 21 of 22 ENSP00000504985.1 A0A7P0Z439
CUL4BENST00000679432.1 linkn.*1776A>T non_coding_transcript_exon_variant Exon 21 of 22 ENSP00000505343.1 A0A7P0T8W4
CUL4BENST00000680918.1 linkn.*1483A>T non_coding_transcript_exon_variant Exon 17 of 18 ENSP00000505955.1 A0A7P0Z4G9
CUL4BENST00000681080.1 linkn.*1776A>T non_coding_transcript_exon_variant Exon 19 of 20 ENSP00000505898.1 A0A7P0Z4E4
CUL4BENST00000681189.1 linkn.*733A>T non_coding_transcript_exon_variant Exon 19 of 20 ENSP00000505973.1 A0A7P0TAF9
CUL4BENST00000681333.1 linkn.*3460A>T non_coding_transcript_exon_variant Exon 16 of 17 ENSP00000505739.1 A0A7P0T9R8
CUL4BENST00000681908.1 linkn.*739A>T non_coding_transcript_exon_variant Exon 19 of 20 ENSP00000505777.1 A0A7P0T9P5
CUL4BENST00000673919.1 linkn.*2014A>T 3_prime_UTR_variant Exon 20 of 21 ENSP00000500994.1 A0A669KAU9
CUL4BENST00000674073.2 linkn.*123A>T 3_prime_UTR_variant Exon 17 of 18 ENSP00000501262.2 A0A669KBG9
CUL4BENST00000679405.1 linkn.*1776A>T 3_prime_UTR_variant Exon 21 of 22 ENSP00000504985.1 A0A7P0Z439
CUL4BENST00000679432.1 linkn.*1776A>T 3_prime_UTR_variant Exon 21 of 22 ENSP00000505343.1 A0A7P0T8W4
CUL4BENST00000680918.1 linkn.*1483A>T 3_prime_UTR_variant Exon 17 of 18 ENSP00000505955.1 A0A7P0Z4G9
CUL4BENST00000681080.1 linkn.*1776A>T 3_prime_UTR_variant Exon 19 of 20 ENSP00000505898.1 A0A7P0Z4E4
CUL4BENST00000681189.1 linkn.*733A>T 3_prime_UTR_variant Exon 19 of 20 ENSP00000505973.1 A0A7P0TAF9
CUL4BENST00000681333.1 linkn.*3460A>T 3_prime_UTR_variant Exon 16 of 17 ENSP00000505739.1 A0A7P0T9R8
CUL4BENST00000681908.1 linkn.*739A>T 3_prime_UTR_variant Exon 19 of 20 ENSP00000505777.1 A0A7P0T9P5

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.12e-7
AC:
1
AN:
1097026
Hom.:
0
Cov.:
29
AF XY:
0.00000276
AC XY:
1
AN XY:
362606
show subpopulations
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:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Nov 09, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
24
DANN
Benign
0.93
DEOGEN2
Benign
0.26
.;.;T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.41
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.41
.;.;N
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.6
N;N;N
REVEL
Benign
0.24
Sift
Benign
0.72
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.018
B;.;B
Vest4
0.52
MutPred
0.49
.;.;Loss of phosphorylation at Y874 (P = 0.0457);
MVP
0.89
MPC
1.5
ClinPred
0.85
D
GERP RS
5.5
Varity_R
0.54
gMVP
0.80

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: chrX-119663982; API