13-113210023-C-T

Position:

• chr13-113210023-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001008895.4(CUL4A):​c.199C>T​(p.His67Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,374,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CUL4A NM_001008895.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.985

Genes affected

CUL4A (HGNC:2554): (cullin 4A) CUL4A is the ubiquitin ligase component of a multimeric complex involved in the degradation of DNA damage-response proteins (Liu et al., 2009 [PubMed 19481525]).[supplied by OMIM, Oct 2009]

CUL4A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24979687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4A	NM_001008895.4	c.199C>T	p.His67Tyr	missense_variant	2/20	ENST00000375440.9	NP_001008895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4A	ENST00000375440.9	c.199C>T	p.His67Tyr	missense_variant	2/20	1	NM_001008895.4	ENSP00000364589.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1374222 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 678334

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: 9.35e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2024

The c.199C>T (p.H67Y) alteration is located in exon 2 (coding exon 2) of the CUL4A gene. This alteration results from a C to T substitution at nucleotide position 199, causing the histidine (H) at amino acid position 67 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.011	D;D
Polyphen		0.018	B;.
Vest4		0.36
MutPred		0.48		Loss of ubiquitination at K65 (P = 0.0787);Loss of ubiquitination at K65 (P = 0.0787);
MVP		0.62
MPC		0.48
ClinPred		0.68	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.30

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: rs1166928710; hg19: chr13-113864337; COSMIC: COSV55812702; COSMIC: COSV55812702;