X-120526797-A-C

Variant names:

• chrX-120526797-A-C
• rs768424127
• NM_001079872.2:c.2652T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001079872.2(CUL4B):​c.2652T>G​(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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D884N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• Publications: 0 publications found

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]

CUL4B Gene-Disease associations (from GenCC):

• X-linked intellectual disability, Cabezas type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
CUL4B	NM_001079872.2	c.2652T>G	p.Asp884Glu	missense_variant	Exon 20 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2706T>G	p.Asp902Glu	missense_variant	Exon 22 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.2667T>G	p.Asp889Glu	missense_variant	Exon 21 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.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
CUL4B	ENST00000371322.11	c.2652T>G	p.Asp884Glu	missense_variant	Exon 20 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2766T>G	p.Asp922Glu	missense_variant	Exon 23 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2706T>G	p.Asp902Glu	missense_variant	Exon 22 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2706T>G	p.Asp902Glu	missense_variant	Exon 23 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2706T>G	p.Asp902Glu	missense_variant	Exon 25 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2667T>G	p.Asp889Glu	missense_variant	Exon 21 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2658T>G	p.Asp886Glu	missense_variant	Exon 20 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2559T>G	p.Asp853Glu	missense_variant	Exon 20 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.2499T>G	p.Asp833Glu	missense_variant	Exon 19 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.2307T>G	p.Asp769Glu	missense_variant	Exon 21 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2118T>G	p.Asp706Glu	missense_variant	Exon 20 of 20	5		ENSP00000360374.3
CUL4B	ENST00000679844.1	c.1989T>G	p.Asp663Glu	missense_variant	Exon 18 of 18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*2099T>G		non_coding_transcript_exon_variant	Exon 21 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*208T>G		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1861T>G		non_coding_transcript_exon_variant	Exon 22 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1861T>G		non_coding_transcript_exon_variant	Exon 22 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1568T>G		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1861T>G		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*818T>G		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3545T>G		non_coding_transcript_exon_variant	Exon 17 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*824T>G		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000505777.1
CUL4B	ENST00000680474.1	c.*98T>G		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505562.1
CUL4B	ENST00000673919.1	n.*2099T>G		3_prime_UTR_variant	Exon 21 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*208T>G		3_prime_UTR_variant	Exon 18 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1861T>G		3_prime_UTR_variant	Exon 22 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1861T>G		3_prime_UTR_variant	Exon 22 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1568T>G		3_prime_UTR_variant	Exon 18 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1861T>G		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*818T>G		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3545T>G		3_prime_UTR_variant	Exon 17 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*824T>G		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183050 AF XY: 0.0000148

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26108

American (AMR) AF: 0.0000573 AC: 2 AN: 34908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19023

East Asian (EAS) AF: 0.00 AC: 0 AN: 29627

South Asian (SAS) AF: 0.00 AC: 0 AN: 53757

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 831698

Other (OTH) AF: 0.00 AC: 0 AN: 45386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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
PhyloP100		1.6
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
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs768424127; hg19: chrX-119660652;