11-47214994-A-T

Variant names:

• chr11-47214994-A-T
• rs981369560
• NM_000107.3:c.-143A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000107.3(DDB2):​c.-143A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000937 in 1,067,088 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: 31)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: DDB2 NM_000107.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.993
• Publications: 0 publications found

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]

DDB2 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group E

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000107.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDB2	NM_000107.3	MANE Select	c.-143A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_000098.1	Q92466-1
	DDB2	NM_000107.3	MANE Select	c.-143A>T		5_prime_UTR	Exon 1 of 10	NP_000098.1	Q92466-1
	DDB2	NM_001399878.1		c.-143A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001386807.1	Q92466-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDB2	ENST00000256996.9	TSL:1 MANE Select	c.-143A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000256996.4	Q92466-1
	DDB2	ENST00000256996.9	TSL:1 MANE Select	c.-143A>T		5_prime_UTR	Exon 1 of 10	ENSP00000256996.4	Q92466-1
	DDB2	ENST00000915751.1		c.-143A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000585810.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.37e-7 AC: 1 AN: 1067088 Hom.: 0 Cov.: 14 AF XY: 0.00000183 AC XY: 1 AN XY: 547132

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25524

American (AMR) AF: 0.00 AC: 0 AN: 43048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22934

East Asian (EAS) AF: 0.00 AC: 0 AN: 37402

South Asian (SAS) AF: 0.00 AC: 0 AN: 77244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4950

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 765314

Other (OTH) AF: 0.00 AC: 0 AN: 47026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		-0.99
PromoterAI		0.015	Neutral

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

Other links and lift over

dbSNP: rs981369560; hg19: chr11-47236545;