NM_022836.4:c.1519A>C

Variant names:

• chr1-113912111-A-C
• rs757797519
• NM_022836.4:c.1519A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022836.4(DCLRE1B):​c.1519A>C​(p.Thr507Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T507I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DCLRE1B NM_022836.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.91
• Publications: 0 publications found

Genes affected

DCLRE1B (HGNC:17641): (DNA cross-link repair 1B) DNA interstrand cross-links prevent strand separation, thereby physically blocking transcription, replication, and segregation of DNA. DCLRE1B is one of several evolutionarily conserved genes involved in repair of interstrand cross-links (Dronkert et al., 2000 [PubMed 10848582]).[supplied by OMIM, Mar 2008]

HIPK1-AS1 (HGNC:50576): (HIPK1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3711658).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022836.4. 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
	DCLRE1B	NM_022836.4	MANE Select	c.1519A>C	p.Thr507Pro	missense	Exon 4 of 4	NP_073747.1	Q9H816
	DCLRE1B	NM_001319946.2		c.1141A>C	p.Thr381Pro	missense	Exon 3 of 3	NP_001306875.1
	DCLRE1B	NM_001319947.2		c.1141A>C	p.Thr381Pro	missense	Exon 4 of 4	NP_001306876.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1B	ENST00000650450.2	MANE Select	c.1519A>C	p.Thr507Pro	missense	Exon 4 of 4	ENSP00000498042.1	Q9H816
	DCLRE1B	ENST00000466480.2	TSL:1	n.*862-21A>C		intron	N/A	ENSP00000497696.1	A0A3B3IT16
	DCLRE1B	ENST00000970516.1		c.1519A>C	p.Thr507Pro	missense	Exon 5 of 5	ENSP00000640575.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.021	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.35		Gain of catalytic residue at T507 (P = 0.0695)
MVP		0.92
MPC		0.70
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.58
Mutation Taster		=89/11	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: rs757797519; hg19: chr1-114454733;