14-69054150-T-C

Variant names:

• chr14-69054150-T-C
• rs2037857752
• NM_003861.3:c.2536A>G

Variant summary

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

The NM_003861.3(DCAF5):​c.2536A>G​(p.Asn846Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DCAF5 NM_003861.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66

Genes affected

DCAF5 (HGNC:20224): (DDB1 and CUL4 associated factor 5) Predicted to be involved in protein ubiquitination. Part of Cul4-RING E3 ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.14534354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCAF5	NM_003861.3	c.2536A>G	p.Asn846Asp	missense_variant	Exon 9 of 9	ENST00000341516.10	NP_003852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCAF5	ENST00000341516.10	c.2536A>G	p.Asn846Asp	missense_variant	Exon 9 of 9	1	NM_003861.3	ENSP00000341351.5
DCAF5	ENST00000557386.5	c.2533A>G	p.Asn845Asp	missense_variant	Exon 9 of 9	1		ENSP00000451845.1
DCAF5	ENST00000554215.5	c.2290A>G	p.Asn764Asp	missense_variant	Exon 9 of 9	1		ENSP00000451551.1
DCAF5	ENST00000556847.5	c.2290A>G	p.Asn764Asp	missense_variant	Exon 9 of 9	5		ENSP00000452052.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2536A>G (p.N846D) alteration is located in exon 9 (coding exon 9) of the DCAF5 gene. This alteration results from a A to G substitution at nucleotide position 2536, causing the asparagine (N) at amino acid position 846 to be replaced by an aspartic acid (D). 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	0.083
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T;.;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.0	L;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.96	N;N;N;N
REVEL	Benign	0.097
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.32	B;.;.;.
Vest4		0.14
MutPred		0.12		Loss of glycosylation at P844 (P = 0.1258);.;.;.;
MVP		0.52
MPC		0.25
ClinPred		0.50	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.085

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: rs2037857752; hg19: chr14-69520867;