rs28381079

chr1-113911976-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022836.4(DCLRE1B):c.1384G>A(p.Asp462Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,614,206 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (30 hom.)
• Consequence: DCLRE1B NM_022836.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.155

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022997558).
• BP6: Variant 1-113911976-G-A is Benign according to our data. Variant chr1-113911976-G-A is described in ClinVar as [Benign]. Clinvar id is 533712.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (2077/152328) while in subpopulation AFR AF= 0.0476 (1979/41560). AF 95% confidence interval is 0.0459. There are 52 homozygotes in gnomad4. There are 1008 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLRE1B	NM_022836.4	c.1384G>A	p.Asp462Asn	missense_variant	4/4	ENST00000650450.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLRE1B	ENST00000650450.2	c.1384G>A	p.Asp462Asn	missense_variant	4/4		NM_022836.4	P1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2066 AN: 152210 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00352 AC: 885 AN: 251430 Hom.: 17 AF XY: 0.00236 AC XY: 321 AN XY: 135890

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00127 AC: 1861 AN: 1461878 Hom.: 30 Cov.: 31 AF XY: 0.00107 AC XY: 778 AN XY: 727240

Gnomad4 AFR exome AF: 0.0446

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.0136 AC: 2077 AN: 152328 Hom.: 52 Cov.: 32 AF XY: 0.0135 AC XY: 1008 AN XY: 74498

Gnomad4 AFR AF: 0.0476

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00530 Hom.: 61

Bravo AF: 0.0162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0486 AC: 214

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00448 AC: 544

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hoyeraal-Hreidarsson syndrome;C3502105:Autosomal recessive dyskeratosis congenita Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.1
Dann	Uncertain	0.98
DEOGEN2	Benign	0.066	T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.067	N
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.22	N;.;.
REVEL	Benign	0.064
Sift	Benign	0.37	T;.;.
Sift4G	Benign	0.24	T;.;.
Polyphen		0.0	B;.;B
Vest4		0.073
MVP		0.37
MPC		0.15
ClinPred		0.0030	T
GERP RS		1.9
Varity_R		0.021
gMVP		0.12

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: rs28381079; hg19: chr1-114454598;