X-120526772-A-T

Variant names:

• chrX-120526772-A-T
• NM_001079872.2:c.2677T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001079872.2(CUL4B):​c.2677T>A​(p.Tyr893Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (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: 8.94

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2677T>A	p.Tyr893Asn	missense_variant	Exon 20 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2731T>A	p.Tyr911Asn	missense_variant	Exon 22 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.2692T>A	p.Tyr898Asn	missense_variant	Exon 21 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.2143T>A	p.Tyr715Asn	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.2677T>A	p.Tyr893Asn	missense_variant	Exon 20 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2791T>A	p.Tyr931Asn	missense_variant	Exon 23 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2731T>A	p.Tyr911Asn	missense_variant	Exon 22 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2731T>A	p.Tyr911Asn	missense_variant	Exon 23 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2731T>A	p.Tyr911Asn	missense_variant	Exon 25 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2692T>A	p.Tyr898Asn	missense_variant	Exon 21 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2683T>A	p.Tyr895Asn	missense_variant	Exon 20 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2584T>A	p.Tyr862Asn	missense_variant	Exon 20 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.2524T>A	p.Tyr842Asn	missense_variant	Exon 19 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.2332T>A	p.Tyr778Asn	missense_variant	Exon 21 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2143T>A	p.Tyr715Asn	missense_variant	Exon 20 of 20	5		ENSP00000360374.3
CUL4B	ENST00000679844.1	c.2014T>A	p.Tyr672Asn	missense_variant	Exon 18 of 18			ENSP00000505239.1
CUL4B	ENST00000680474	c.*123T>A		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505562.1
CUL4B	ENST00000673919.1	n.*2124T>A		non_coding_transcript_exon_variant	Exon 21 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*233T>A		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1886T>A		non_coding_transcript_exon_variant	Exon 22 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1886T>A		non_coding_transcript_exon_variant	Exon 22 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1593T>A		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1886T>A		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*843T>A		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3570T>A		non_coding_transcript_exon_variant	Exon 17 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*849T>A		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*2124T>A		3_prime_UTR_variant	Exon 21 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*233T>A		3_prime_UTR_variant	Exon 18 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1886T>A		3_prime_UTR_variant	Exon 22 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1886T>A		3_prime_UTR_variant	Exon 22 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1593T>A		3_prime_UTR_variant	Exon 18 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1886T>A		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*843T>A		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3570T>A		3_prime_UTR_variant	Exon 17 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*849T>A		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1065439 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 336097

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: 0.00

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

not provided Uncertain:1

Dec 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;.;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.90
MutPred		0.48		.;.;Loss of stability (P = 0.0439);
MVP		1.0
MPC		4.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.97

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-119660627;