11-61300817-T-G

Variant names:

• chr11-61300817-T-G
• NM_001923.5:c.3331A>C

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.3331A>C​(p.Asn1111His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1111K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDB1 NM_001923.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.69
• Publications: 0 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=0.23329052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDB1	NM_001923.5	c.3331A>C	p.Asn1111His	missense_variant	Exon 26 of 27	ENST00000301764.12	NP_001914.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDB1	ENST00000301764.12	c.3331A>C	p.Asn1111His	missense_variant	Exon 26 of 27	1	NM_001923.5	ENSP00000301764.7
DDB1	ENST00000540166.5	n.*56A>C		non_coding_transcript_exon_variant	Exon 28 of 29	2		ENSP00000440269.1
DDB1	ENST00000540166.5	n.*56A>C		3_prime_UTR_variant	Exon 28 of 29	2		ENSP00000440269.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 11, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Benign	0.092	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.32		Loss of stability (P = 0.0925);
MVP		0.58
MPC		1.5
ClinPred		0.63	D
GERP RS		5.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.55
gMVP		0.59
Mutation Taster		=66/34	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

hg19: chr11-61068289;