9-34107396-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015397.4(DCAF12):c.503A>G(p.Tyr168Cys) 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: 32)
• Consequence: DCAF12 NM_015397.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.42

Genes affected

DCAF12 (HGNC:19911): (DDB1 and CUL4 associated factor 12) This gene encodes a WD repeat-containing protein that interacts with the COP9 signalosome, a macromolecular complex that interacts with cullin-RING E3 ligases and regulates their activity by hydrolyzing cullin-Nedd8 conjugates. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCAF12	NM_015397.4	c.503A>G	p.Tyr168Cys	missense_variant	3/9	ENST00000361264.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCAF12	ENST00000361264.9	c.503A>G	p.Tyr168Cys	missense_variant	3/9	1	NM_015397.4	P1
DCAF12	ENST00000396990.6	c.449A>G	p.Tyr150Cys	missense_variant	3/5	3
DCAF12	ENST00000450964.1	c.440A>G	p.Tyr147Cys	missense_variant	3/5	5
DCAF12	ENST00000463286.1	n.647A>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Mar 31, 2023

The c.503A>G (p.Y168C) alteration is located in exon 3 (coding exon 3) of the DCAF12 gene. This alteration results from a A to G substitution at nucleotide position 503, causing the tyrosine (Y) at amino acid position 168 to be replaced by a cysteine (C). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Uncertain	2.9	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.5	D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.82		Loss of catalytic residue at Y168 (P = 0.0751);.;.;
MVP		0.87
MPC		1.4
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.87

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: rs879743911; hg19: chr9-34107394;