rs750772

Positions:

• chr2-17786319-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001130009.3(GEN1):​c.*4380A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,162 control chromosomes in the GnomAD database, including 3,481 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (3481 hom., cov: 33)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: GEN1 NM_001130009.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.896

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]

LOC105373449 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEN1	NM_001130009.3	c.*4380A>G		3_prime_UTR_variant	14/14	ENST00000381254.7	NP_001123481.3
LOC105373449	XR_939762.3	n.408+12832T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GEN1	ENST00000381254.7	c.*4380A>G		3_prime_UTR_variant	14/14	5	NM_001130009.3	ENSP00000370653	P1
GEN1	ENST00000317402.11	c.*4380A>G		3_prime_UTR_variant	14/14	2		ENSP00000318977	P1
SMC6	ENST00000402989.5	c.-6+1496T>C		intron_variant		2		ENSP00000384539	P1
SMC6	ENST00000428868.1	c.-6+1496T>C		intron_variant		4		ENSP00000415352

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27164 AN: 152036 Hom.: 3471 Cov.: 33

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0673

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0822

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.156

GnomAD4 exome AF: 0.125 AC: 1 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

Gnomad4 NFE exome AF: 0.125

GnomAD4 genome AF: 0.179 AC: 27215 AN: 152154 Hom.: 3481 Cov.: 33 AF XY: 0.175 AC XY: 13048 AN XY: 74396

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.0675

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.0822

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.155

Alfa AF: 0.129 Hom.: 715

Bravo AF: 0.189

Asia WGS AF: 0.101 AC: 349 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.48

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: rs750772; hg19: chr2-17967586;