4-41982754-A-G

Position:

• chr4-41982754-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001029955.4(DCAF4L1):​c.962A>G​(p.His321Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: DCAF4L1 NM_001029955.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64

Genes affected

DCAF4L1 (HGNC:27723): (DDB1 and CUL4 associated factor 4 like 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.288221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCAF4L1	NM_001029955.4	c.962A>G	p.His321Arg	missense_variant	1/1	ENST00000333141.7	NP_001025126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCAF4L1	ENST00000333141.7	c.962A>G	p.His321Arg	missense_variant	1/1	6	NM_001029955.4	ENSP00000327796.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461890 Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6 AN XY: 727246

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Jun 02, 2023

The c.962A>G (p.H321R) alteration is located in exon 1 (coding exon 1) of the DCAF4L1 gene. This alteration results from a A to G substitution at nucleotide position 962, causing the histidine (H) at amino acid position 321 to be replaced by an arginine (R). 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	0.20
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.16
Sift	Benign	0.082	T
Sift4G	Benign	0.067	T
Polyphen		0.59	P
Vest4		0.42
MutPred		0.52		Gain of glycosylation at Y317 (P = 0.0342);
MVP		0.093
MPC		1.9
ClinPred		1.0	D
GERP RS		0.97
Varity_R		0.32
gMVP		0.42

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: rs752221463; hg19: chr4-41984771;