chr13-113219039-C-T

Variant names:

• chr13-113219039-C-T
• rs1379704929
• NM_001008895.4:c.359C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001354941.2(CUL4A):​c.-75C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000813 in 1,598,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: CUL4A NM_001354941.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090441465).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4A	NM_001008895.4	c.359C>T	p.Pro120Leu	missense_variant	Exon 3 of 20	ENST00000375440.9	NP_001008895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4A	ENST00000375440.9	c.359C>T	p.Pro120Leu	missense_variant	Exon 3 of 20	1	NM_001008895.4	ENSP00000364589.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000761 AC: 11 AN: 1446410 Hom.: 0 Cov.: 28 AF XY: 0.00000973 AC XY: 7 AN XY: 719600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000235

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.359C>T (p.P120L) alteration is located in exon 3 (coding exon 3) of the CUL4A gene. This alteration results from a C to T substitution at nucleotide position 359, causing the proline (P) at amino acid position 120 to be replaced by a leucine (L). 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	0.085
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.71
DEOGEN2	Benign	0.015	.;T;.;.;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.81	.;T;T;.;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.090	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.61	.;.;.;.;N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.23	N;N;N;.;N;.
REVEL	Benign	0.11
Sift	Benign	0.31	T;T;T;.;T;.
Sift4G	Benign	0.30	T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.
Vest4		0.27
MutPred		0.45		.;.;.;.;Gain of catalytic residue at D124 (P = 0.0107);Gain of catalytic residue at D124 (P = 0.0107);
MVP		0.51
MPC		0.41
ClinPred		0.30	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1379704929; hg19: chr13-113873353;