14-72940358-A-G

Position:

• chr14-72940358-A-G

Variant summary

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

The NM_015604.4(DCAF4):​c.332A>G​(p.Glu111Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCAF4 NM_015604.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

Genes affected

DCAF4 (HGNC:20229): (DDB1 and CUL4 associated factor 4) This gene encodes a WD repeat-containing protein that interacts with the Cul4-Ddb1 E3 ligase macromolecular complex. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCAF4	NM_015604.4	c.332A>G	p.Glu111Gly	missense_variant	4/14	ENST00000358377.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCAF4	ENST00000358377.7	c.332A>G	p.Glu111Gly	missense_variant	4/14	1	NM_015604.4	A1

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

Dec 17, 2021

The c.332A>G (p.E111G) alteration is located in exon 4 (coding exon 3) of the DCAF4 gene. This alteration results from a A to G substitution at nucleotide position 332, causing the glutamic acid (E) at amino acid position 111 to be replaced by a glycine (G). 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	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T;.;.;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.7	M;.;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D;D;T;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		0.86	P;D;.;.;.;.
Vest4		0.51
MutPred		0.36		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);.;Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);.;
MVP		0.83
MPC		0.46
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.22
gMVP		0.40

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: rs1567305536; hg19: chr14-73407066;