rs869312794

Variant names:

• chr2-17772788-A-G
• rs869312794
• NM_001130009.3:c.953+4A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001130009.3(GEN1):​c.953+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,601,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GEN1 NM_001130009.3 splice_region, intron
• Scores: Splicing: ADA: 0.9648
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.13
• Publications: 0 publications found

Genes affected

GEN1 (HGNC:26881): (GEN1 Holliday junction 5' flap endonuclease) This gene encodes a member of the Rad2/xeroderma pigmentosum group G nuclease family, whose members are characterized by N-terminal and internal xeroderma pigmentosum group G nuclease domains followed by helix-hairpin-helix domains and disordered C-terminal domains. The protein encoded by this gene is involved in resolution of Holliday junctions, which are intermediate four-way structures that covalently link DNA during homologous recombination and double-strand break repair. The protein resolves Holliday junctions by creating dual incisions across the junction to produce nicked duplex products that can be ligated. In addition, this protein has been found to localize to centrosomes where it has been implicated in regulation of centrosome integrity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

SMC6 (HGNC:20466): (structural maintenance of chromosomes 6) Enables ubiquitin protein ligase binding activity. Involved in several processes, including cellular senescence; positive regulation of chromosome segregation; and telomere maintenance via recombination. Located in chromosome and nuclear body. Part of Smc5-Smc6 complex. [provided by Alliance of Genome Resources, Apr 2022]

LOC105373449 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130009.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEN1	NM_001130009.3	MANE Select	c.953+4A>G		splice_region intron	N/A	NP_001123481.3
	GEN1	NM_182625.5		c.953+4A>G		splice_region intron	N/A	NP_872431.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEN1	ENST00000381254.7	TSL:5 MANE Select	c.953+4A>G		splice_region intron	N/A	ENSP00000370653.2
	SMC6	ENST00000402989.5	TSL:2	c.-6+15027T>C		intron	N/A	ENSP00000384539.1
	GEN1	ENST00000317402.11	TSL:2	c.953+4A>G		splice_region intron	N/A	ENSP00000318977.7

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239384 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449144 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720848

African (AFR) AF: 0.00 AC: 0 AN: 32900

American (AMR) AF: 0.00 AC: 0 AN: 42348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 84634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105736

Other (OTH) AF: 0.00 AC: 0 AN: 59756

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74236

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.83
PhyloP100		1.1
PromoterAI		-0.052	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.35		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869312794; hg19: chr2-17954055;