chr19-17319645-G-A

Position:

• chr19-17319645-G-A

Variant summary

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

The NM_024050.6(DDA1):​c.298G>A​(p.Glu100Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DDA1 NM_024050.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

DDA1 (HGNC:28360): (DET1 and DDB1 associated 1) Involved in protein polyubiquitination. Part of Cul4-RING E3 ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

DDA1 (HGNC:):

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=0.35196418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDA1	NM_024050.6	c.298G>A	p.Glu100Lys	missense_variant	5/5	ENST00000359866.9	NP_076955.1
DDA1	XR_007067003.1	n.390G>A		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDA1	ENST00000359866.9	c.298G>A	p.Glu100Lys	missense_variant	5/5	1	NM_024050.6	ENSP00000352928.3
DDA1	ENST00000593466.5	n.298G>A		non_coding_transcript_exon_variant	5/6	3		ENSP00000473086.1
DDA1	ENST00000594501.1	n.324G>A		non_coding_transcript_exon_variant	2/2	2
DDA1	ENST00000596582.1	n.298G>A		non_coding_transcript_exon_variant	5/6	3		ENSP00000472171.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417912 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 701112

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.18e-7

Gnomad4 OTH exome AF: 0.00

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

Oct 08, 2024

The c.298G>A (p.E100K) alteration is located in exon 5 (coding exon 5) of the DDA1 gene. This alteration results from a G to A substitution at nucleotide position 298, causing the glutamic acid (E) at amino acid position 100 to be replaced by a lysine (K). 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	0.15
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.024	D
Sift4G	Benign	0.14	T
Polyphen		0.98	D
Vest4		0.53
MutPred		0.12		Gain of ubiquitination at E100 (P = 0.0031);
MVP		0.34
MPC		1.0
ClinPred		0.84	D
GERP RS		4.6
Varity_R		0.21
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-17430454;