rs16981869

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001130009.3(GEN1):c.428A>G(p.Asn143Ser) variant causes a missense change. The variant allele was found at a frequency of 0.105 in 1,613,922 control chromosomes in the GnomAD database, including 9,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.14 ( 1705 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8134 hom. )

Consequence

GEN1
NM_001130009.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.12

Variant links:

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]

GEN1 links:

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]

SMC6 links:

LOC105373449 (HGNC:):

LOC105373449 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018734038).

BP6

Variant 2-17764976-A-G is Benign according to our data. Variant chr2-17764976-A-G is described in ClinVar as [Benign]. Clinvar id is 1167514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEN1	NM_001130009.3 link	c.428A>G	p.Asn143Ser	missense_variant	Exon 4 of 14	ENST00000381254.7	NP_001123481.3	Q17RS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEN1	ENST00000381254.7 link	c.428A>G	p.Asn143Ser	missense_variant	Exon 4 of 14	5	NM_001130009.3	ENSP00000370653.2		Q17RS7

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20666

AN:

152058

Hom.:

1703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.235

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.0366

Gnomad SAS

AF:

0.0960

Gnomad FIN

AF:

0.0813

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.123

GnomAD3 exomes

AF:

0.100

AC:

25221

AN:

251450

Hom.:

1544

AF XY:

0.100

AC XY:

13590

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.237

Gnomad AMR exome

AF:

0.0740

Gnomad ASJ exome

AF:

0.0994

Gnomad EAS exome

AF:

0.0348

Gnomad SAS exome

AF:

0.0962

Gnomad FIN exome

AF:

0.0784

Gnomad NFE exome

AF:

0.105

Gnomad OTH exome

AF:

0.0992

GnomAD4 exome

AF:

0.102

AC:

149228

AN:

1461746

Hom.:

8134

Cov.:

AF XY:

0.102

AC XY:

73986

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.241

Gnomad4 AMR exome

AF:

0.0774

Gnomad4 ASJ exome

AF:

0.0990

Gnomad4 EAS exome

AF:

0.0429

Gnomad4 SAS exome

AF:

0.0971

Gnomad4 FIN exome

AF:

0.0794

Gnomad4 NFE exome

AF:

0.102

Gnomad4 OTH exome

AF:

0.104

GnomAD4 genome

AF:

0.136

AC:

20690

AN:

152176

Hom.:

1705

Cov.:

AF XY:

0.134

AC XY:

9955

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.234

Gnomad4 AMR

AF:

0.102

Gnomad4 ASJ

AF:

0.102

Gnomad4 EAS

AF:

0.0367

Gnomad4 SAS

AF:

0.0969

Gnomad4 FIN

AF:

0.0813

Gnomad4 NFE

AF:

0.105

Gnomad4 OTH

AF:

0.122

Alfa

AF:

0.106

Hom.:

2085

Bravo

AF:

0.141

TwinsUK

AF:

0.103

AC:

382

ALSPAC

AF:

0.0937

AC:

361

ESP6500AA

AF:

0.229

AC:

1008

ESP6500EA

AF:

0.103

AC:

883

ExAC

AF:

0.104

AC:

12682

Asia WGS

AF:

0.0700

AC:

242

AN:

3478

EpiCase

AF:

0.102

EpiControl

AF:

0.105

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

.;D

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Uncertain

0.29

Sift

Benign

0.030

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

0.81

P;P

Vest4

0.20

MPC

0.21

ClinPred

0.089

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over