X-120530127-T-A

Position:

• chrX-120530127-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CUL4B. . Gene score misZ 3.7714 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability, Cabezas type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41170964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2567A>T	p.Tyr856Phe	missense_variant	19/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2621A>T	p.Tyr874Phe	missense_variant	21/22		NP_003579.3
CUL4B	NM_001330624.2	c.2582A>T	p.Tyr861Phe	missense_variant	20/21		NP_001317553.1
CUL4B	NM_001369145.1	c.2033A>T	p.Tyr678Phe	missense_variant	19/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2567A>T	p.Tyr856Phe	missense_variant	19/20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2681A>T	p.Tyr894Phe	missense_variant	22/23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2621A>T	p.Tyr874Phe	missense_variant	21/22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2621A>T	p.Tyr874Phe	missense_variant	22/23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2621A>T	p.Tyr874Phe	missense_variant	24/25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2582A>T	p.Tyr861Phe	missense_variant	20/21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2573A>T	p.Tyr858Phe	missense_variant	19/20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2474A>T	p.Tyr825Phe	missense_variant	19/20			ENSP00000506288.1
CUL4B	ENST00000679927.1	c.2222A>T	p.Tyr741Phe	missense_variant	20/21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2033A>T	p.Tyr678Phe	missense_variant	19/20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.2009A>T	p.Tyr670Phe	missense_variant	18/20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1904A>T	p.Tyr635Phe	missense_variant	17/18			ENSP00000505239.1
CUL4B	ENST00000404115.8	c.2439+2295A>T		intron_variant		1		ENSP00000384109.4
CUL4B	ENST00000673919.1	n.*2014A>T		non_coding_transcript_exon_variant	20/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*123A>T		non_coding_transcript_exon_variant	17/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1776A>T		non_coding_transcript_exon_variant	21/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1776A>T		non_coding_transcript_exon_variant	21/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1483A>T		non_coding_transcript_exon_variant	17/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1776A>T		non_coding_transcript_exon_variant	19/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*733A>T		non_coding_transcript_exon_variant	19/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3460A>T		non_coding_transcript_exon_variant	16/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*739A>T		non_coding_transcript_exon_variant	19/20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*2014A>T		3_prime_UTR_variant	20/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*123A>T		3_prime_UTR_variant	17/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1776A>T		3_prime_UTR_variant	21/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1776A>T		3_prime_UTR_variant	21/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1483A>T		3_prime_UTR_variant	17/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1776A>T		3_prime_UTR_variant	19/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*733A>T		3_prime_UTR_variant	19/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3460A>T		3_prime_UTR_variant	16/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*739A>T		3_prime_UTR_variant	19/20			ENSP00000505777.1

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

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

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 09, 2023

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;