1-113907040-T-C

Variant names:

• chr1-113907040-T-C
• rs3761936
• NM_022836.4:c.234T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022836.4(DCLRE1B):​c.234T>C​(p.His78His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,613,556 control chromosomes in the GnomAD database, including 33,593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2965 hom., cov: 30)
  • Exomes 𝑓: 0.19 (30628 hom.)
• Consequence: DCLRE1B NM_022836.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.133
• Publications: 34 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]

DCLRE1B Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal recessive 8

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-113907040-T-C is Benign according to our data. Variant chr1-113907040-T-C is described in ClinVar as Benign. ClinVar VariationId is 1169794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.133 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

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.234T>C	p.His78His	synonymous	Exon 2 of 4	NP_073747.1	Q9H816
	DCLRE1B	NM_001363690.2		c.234T>C	p.His78His	synonymous	Exon 2 of 5	NP_001350619.1
	DCLRE1B	NM_001319946.2		c.-23-969T>C		intron	N/A	NP_001306875.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1B	ENST00000650450.2	MANE Select	c.234T>C	p.His78His	synonymous	Exon 2 of 4	ENSP00000498042.1	Q9H816
	DCLRE1B	ENST00000466480.2	TSL:1	n.190-969T>C		intron	N/A	ENSP00000497696.1	A0A3B3IT16
	DCLRE1B	ENST00000970516.1		c.234T>C	p.His78His	synonymous	Exon 3 of 5	ENSP00000640575.1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24537 AN: 151616 Hom.: 2973 Cov.: 30

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.224 AC: 56379 AN: 251464 AF XY: 0.213

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.593

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.186 AC: 271656 AN: 1461824 Hom.: 30628 Cov.: 35 AF XY: 0.183 AC XY: 133407 AN XY: 727218

African (AFR) AF: 0.0341 AC: 1143 AN: 33480

American (AMR) AF: 0.421 AC: 18824 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3391 AN: 26134

East Asian (EAS) AF: 0.562 AC: 22302 AN: 39694

South Asian (SAS) AF: 0.139 AC: 12023 AN: 86258

European-Finnish (FIN) AF: 0.185 AC: 9863 AN: 53414

Middle Eastern (MID) AF: 0.174 AC: 1003 AN: 5768

European-Non Finnish (NFE) AF: 0.172 AC: 191782 AN: 1111956

Other (OTH) AF: 0.188 AC: 11325 AN: 60396

GnomAD4 genome AF: 0.162 AC: 24526 AN: 151732 Hom.: 2965 Cov.: 30 AF XY: 0.166 AC XY: 12333 AN XY: 74154

African (AFR) AF: 0.0389 AC: 1609 AN: 41364

American (AMR) AF: 0.313 AC: 4770 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3464

East Asian (EAS) AF: 0.583 AC: 2994 AN: 5136

South Asian (SAS) AF: 0.154 AC: 741 AN: 4804

European-Finnish (FIN) AF: 0.182 AC: 1912 AN: 10520

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11554 AN: 67900

Other (OTH) AF: 0.178 AC: 372 AN: 2094

Alfa AF: 0.163 Hom.: 4814

Bravo AF: 0.173

Asia WGS AF: 0.318 AC: 1102 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.164

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hoyeraal-Hreidarsson syndrome;C3502105:Autosomal recessive dyskeratosis congenita (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.6
DANN	Benign	0.69
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3761936; hg19: chr1-114449662; COSMIC: COSV56724858; COSMIC: COSV56724858;