NM_001923.5:c.2683A>G

Variant names:

• chr11-61304014-T-C
• rs765613377
• NM_001923.5:c.2683A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001923.5(DDB1):​c.2683A>G​(p.Thr895Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DDB1 NM_001923.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18
• Publications: 1 publications found

Genes affected

DDB1 (HGNC:2717): (damage specific DNA binding protein 1) The protein encoded by this gene is the large subunit (p127) of the heterodimeric DNA damage-binding (DDB) complex while another protein (p48) forms the small subunit. This protein complex functions in nucleotide-excision repair and binds to DNA following UV damage. Defective activity of this complex causes the repair defect in patients with xeroderma pigmentosum complementation group E (XPE) - an autosomal recessive disorder characterized by photosensitivity and early onset of carcinomas. However, it remains for mutation analysis to demonstrate whether the defect in XPE patients is in this gene or the gene encoding the small subunit. In addition, Best vitelliform mascular dystrophy is mapped to the same region as this gene on 11q, but no sequence alternations of this gene are demonstrated in Best disease patients. The protein encoded by this gene also functions as an adaptor molecule for the cullin 4 (CUL4) ubiquitin E3 ligase complex by facilitating the binding of substrates to this complex and the ubiquitination of proteins. [provided by RefSeq, May 2012]

DDB1 Gene-Disease associations (from GenCC):

• White-Kernohan syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073556334).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001923.5. 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
	DDB1	NM_001923.5	MANE Select	c.2683A>G	p.Thr895Ala	missense	Exon 22 of 27	NP_001914.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDB1	ENST00000301764.12	TSL:1 MANE Select	c.2683A>G	p.Thr895Ala	missense	Exon 22 of 27	ENSP00000301764.7	Q16531-1
	DDB1	ENST00000540166.5	TSL:2	n.2683A>G		non_coding_transcript_exon	Exon 24 of 29	ENSP00000440269.1	F5GY55
	DDB1	ENST00000954153.1		c.2815A>G	p.Thr939Ala	missense	Exon 23 of 28	ENSP00000624212.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251418 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	White-Kernohan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.70
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.8	N
PhyloP100		4.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.075
Sift	Benign	0.83	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.21		Gain of sheet (P = 0.0827)
MVP		0.36
MPC		1.4
ClinPred		0.067	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.39
gMVP		0.21
Mutation Taster		=63/37	polymorphism

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: rs765613377; hg19: chr11-61071486;