rs1556196865

Positions:

• chrX-120536932-G-T

Variant summary

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

The NM_001079872.2(CUL4B):​c.2041C>A​(p.Pro681Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56

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 (HGNC:):

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=0.36016858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2041C>A	p.Pro681Thr	missense_variant	15/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2095C>A	p.Pro699Thr	missense_variant	17/22		NP_003579.3
CUL4B	NM_001330624.2	c.2056C>A	p.Pro686Thr	missense_variant	16/21		NP_001317553.1
CUL4B	NM_001369145.1	c.1507C>A	p.Pro503Thr	missense_variant	15/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2041C>A	p.Pro681Thr	missense_variant	15/20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2155C>A	p.Pro719Thr	missense_variant	18/23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2095C>A	p.Pro699Thr	missense_variant	17/22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2095C>A	p.Pro699Thr	missense_variant	18/23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2095C>A	p.Pro699Thr	missense_variant	20/25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2056C>A	p.Pro686Thr	missense_variant	16/21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2047C>A	p.Pro683Thr	missense_variant	15/20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1948C>A	p.Pro650Thr	missense_variant	15/20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.2041C>A	p.Pro681Thr	missense_variant	15/19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.1696C>A	p.Pro566Thr	missense_variant	16/21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.1507C>A	p.Pro503Thr	missense_variant	15/20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.1483C>A	p.Pro495Thr	missense_variant	14/20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1378C>A	p.Pro460Thr	missense_variant	13/18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*1488C>A		non_coding_transcript_exon_variant	16/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.1483C>A		non_coding_transcript_exon_variant	14/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1250C>A		non_coding_transcript_exon_variant	17/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1250C>A		non_coding_transcript_exon_variant	17/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*957C>A		non_coding_transcript_exon_variant	13/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1250C>A		non_coding_transcript_exon_variant	15/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*207C>A		non_coding_transcript_exon_variant	15/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*2934C>A		non_coding_transcript_exon_variant	12/17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.1483C>A		non_coding_transcript_exon_variant	14/17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.*213C>A		non_coding_transcript_exon_variant	15/20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*1488C>A		3_prime_UTR_variant	16/21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*1250C>A		3_prime_UTR_variant	17/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1250C>A		3_prime_UTR_variant	17/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*957C>A		3_prime_UTR_variant	13/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1250C>A		3_prime_UTR_variant	15/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*207C>A		3_prime_UTR_variant	15/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*2934C>A		3_prime_UTR_variant	12/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*213C>A		3_prime_UTR_variant	15/20			ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.44e-7 AC: 1 AN: 1059427 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 331995

Gnomad4 AFR exome AF: 0.0000390

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: 0.00

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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Uncertain	0.50	.;.;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	.;.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.15
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.26
MutPred		0.45		.;.;Loss of catalytic residue at P698 (P = 0.0121);
MVP		0.83
MPC		1.7
ClinPred		0.68	D
GERP RS		2.9
Varity_R		0.46
gMVP		0.49

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

Other links and lift over

dbSNP: rs1556196865; hg19: chrX-119670787;