rs143049891

chr11-47238177-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000107.3(DDB2):c.1228G>A(p.Ala410Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,610,774 control chromosomes in the GnomAD database, including 19 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (19 hom.)
• Consequence: DDB2 NM_000107.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 1.19

Genes affected

DDB2 (HGNC:2718): (damage specific DNA binding protein 2) This gene encodes a protein that is necessary for the repair of ultraviolet light-damaged DNA. This protein is the smaller subunit of a heterodimeric protein complex that participates in nucleotide excision repair, and this complex mediates the ubiquitylation of histones H3 and H4, which facilitates the cellular response to DNA damage. This subunit appears to be required for DNA binding. Mutations in this gene cause xeroderma pigmentosum complementation group E, a recessive disease that is characterized by an increased sensitivity to UV light and a high predisposition for skin cancer development, in some cases accompanied by neurological abnormalities. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008513182).
• BP6: Variant 11-47238177-G-A is Benign according to our data. Variant chr11-47238177-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133961.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, not_provided=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00253 (385/152308) while in subpopulation NFE AF= 0.00395 (269/68016). AF 95% confidence interval is 0.00357. There are 0 homozygotes in gnomad4. There are 179 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDB2	NM_000107.3	c.1228G>A	p.Ala410Thr	missense_variant	9/10	ENST00000256996.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDB2	ENST00000256996.9	c.1228G>A	p.Ala410Thr	missense_variant	9/10	1	NM_000107.3	P1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00255 AC: 624 AN: 244966 Hom.: 2 AF XY: 0.00233 AC XY: 308 AN XY: 132272

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00215

Gnomad NFE exome AF: 0.00430

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00378 AC: 5520 AN: 1458466 Hom.: 19 Cov.: 33 AF XY: 0.00368 AC XY: 2668 AN XY: 725198

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000304

Gnomad4 FIN exome AF: 0.00220

Gnomad4 NFE exome AF: 0.00458

Gnomad4 OTH exome AF: 0.00335

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74486

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00395

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00336 Hom.: 0

Bravo AF: 0.00264

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00282 AC: 343

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	DDB2: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DDB2 p.Ala410Thr variant was not identified in the literature nor was it identified in LOVD 3.0 or Cosmic. The variant was identified in dbSNP (ID: rs143049891) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 690 of 276356 chromosomes (2 homozygous) at a frequency of 0.002497 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 526 of 126090 chromosomes (freq: 0.004172), European (Finnish) in 52 of 24444 chromosomes (freq: 0.002127), Other in 14 of 7086 chromosomes (freq: 0.001976), Latino in 66 of 34698 chromosomes (freq: 0.001902), African in 27 of 24524 chromosomes (freq: 0.001101) and South Asian in 5 of 29572 chromosomes (freq: 0.000169), but was not observed in the Ashkenazi Jewish, or East Asian populations. The p.Ala410 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	This variant is associated with the following publications: (PMID: 24728327) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 07, 2023	- -

Xeroderma pigmentosum, group E Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Xeroderma pigmentosum Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 12, 2021

- -

DDB2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.84
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.11	N;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.18
MVP		0.36
MPC		0.36
ClinPred		0.021	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.59

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: rs143049891; hg19: chr11-47259728; COSMIC: COSV104563756; COSMIC: COSV104563756;