10-14899187-G-A

Variant summary

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

The ENST00000378289.8(DCLRE1C):c.1282C>T(p.Arg428Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 701,848 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (9 hom.)
• Consequence: DCLRE1C ENST00000378289.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0110

Genes affected

DCLRE1C (HGNC:17642): (DNA cross-link repair 1C) This gene encodes a nuclear protein that is involved in V(D)J recombination and DNA repair. The encoded protein has single-strand-specific 5'-3' exonuclease activity; it also exhibits endonuclease activity on 5' and 3' overhangs and hairpins. The protein also functions in the regulation of the cell cycle in response to DNA damage. Mutations in this gene can cause Athabascan-type severe combined immunodeficiency (SCIDA) and Omenn syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

SUV39H2 (HGNC:17287): (SUV39H2 histone lysine methyltransferase) Enables S-adenosyl-L-methionine binding activity; histone methyltransferase activity (H3-K9 specific); and zinc ion binding activity. Involved in chromatin assembly or disassembly and chromatin remodeling. Acts upstream of or within cellular response to hypoxia and negative regulation of transcription by RNA polymerase II. Located in chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052094758).
• BP6: Variant 10-14899187-G-A is Benign according to our data. Variant chr10-14899187-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1694558.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00289 (440/152218) while in subpopulation NFE AF= 0.00406 (276/68008). AF 95% confidence interval is 0.00367. There are 3 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUV39H2	NM_001193424.2	c.850-352G>A		intron_variant		ENST00000354919.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUV39H2	ENST00000354919.11	c.850-352G>A		intron_variant		5	NM_001193424.2	P1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152100 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00343 AC: 438 AN: 127866 Hom.: 4 AF XY: 0.00356 AC XY: 249 AN XY: 70018

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.000287

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.000559

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00628

GnomAD4 exome AF: 0.00344 AC: 1888 AN: 549630 Hom.: 9 Cov.: 0 AF XY: 0.00349 AC XY: 1039 AN XY: 297552

Gnomad4 AFR exome AF: 0.000570

Gnomad4 AMR exome AF: 0.00294

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.000156

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.000512

Gnomad4 NFE exome AF: 0.00383

Gnomad4 OTH exome AF: 0.00393

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152218 Hom.: 3 Cov.: 32 AF XY: 0.00259 AC XY: 193 AN XY: 74416

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00360 Hom.: 0

Bravo AF: 0.00308

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00441 AC: 17

ExAC AF: 0.00304 AC: 54

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

DCLRE1C: BP4, BS2; SUV39H2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	7.7
Dann	Benign	0.41
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.088
MVP		0.061
ClinPred		0.0026	T
GERP RS		-1.5

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: rs148343292; hg19: chr10-14941186;