rs6076347

Variant names:

• chr20-25418154-G-A
• rs6076347
• NM_021067.5:c.289G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021067.5(GINS1):​c.289G>A​(p.Val97Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 1,598,772 control chromosomes in the GnomAD database, including 158,124 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. Synonymous variant affecting the same amino acid position (i.e. V97V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.35 (10903 hom., cov: 32)
  • Exomes 𝑓: 0.44 (147221 hom.)
• Consequence: GINS1 NM_021067.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.71

Genes affected

GINS1 (HGNC:28980): (GINS complex subunit 1) The yeast heterotetrameric GINS complex is made up of Sld5 (GINS4; MIM 610611), Psf1, Psf2 (GINS2; MIM 610609), and Psf3 (GINS3; MIM 610610). The formation of the GINS complex is essential for the initiation of DNA replication in yeast and Xenopus egg extracts (Ueno et al., 2005 [PubMed 16287864]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.201003E-4).
• BP6: Variant 20-25418154-G-A is Benign according to our data. Variant chr20-25418154-G-A is described in ClinVar as [Benign]. Clinvar id is 1169882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GINS1	NM_021067.5	c.289G>A	p.Val97Ile	missense_variant	Exon 4 of 7	ENST00000262460.5	NP_066545.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GINS1	ENST00000262460.5	c.289G>A	p.Val97Ile	missense_variant	Exon 4 of 7	1	NM_021067.5	ENSP00000262460.4

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53136 AN: 151968 Hom.: 10898 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.00885

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.386

GnomAD3 exomes AF: 0.382 AC: 95925 AN: 251376 Hom.: 20970 AF XY: 0.389 AC XY: 52875 AN XY: 135866

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.487

Gnomad EAS exome AF: 0.00500

Gnomad SAS exome AF: 0.322

Gnomad FIN exome AF: 0.425

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.439 AC: 634508 AN: 1446686 Hom.: 147221 Cov.: 28 AF XY: 0.437 AC XY: 315149 AN XY: 720662

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.00328

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.425

Gnomad4 NFE exome AF: 0.475

Gnomad4 OTH exome AF: 0.413

GnomAD4 genome AF: 0.349 AC: 53147 AN: 152086 Hom.: 10903 Cov.: 32 AF XY: 0.345 AC XY: 25626 AN XY: 74336

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.484

Gnomad4 EAS AF: 0.00887

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.424

Gnomad4 NFE AF: 0.471

Gnomad4 OTH AF: 0.384

Alfa AF: 0.444 Hom.: 41242

Bravo AF: 0.340

TwinsUK AF: 0.478 AC: 1772

ALSPAC AF: 0.485 AC: 1868

ESP6500AA AF: 0.157 AC: 691

ESP6500EA AF: 0.470 AC: 4039

ExAC AF: 0.379 AC: 46020

Asia WGS AF: 0.154 AC: 534 AN: 3478

EpiCase AF: 0.483

EpiControl AF: 0.486

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 65% of patients studied by a panel of primary immunodeficiencies. Number of patients: 62. Only high quality variants are reported. -

Combined immunodeficiency due to GINS1 deficiency Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.3
DANN	Benign	0.62
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.00082	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.77	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.054
Sift	Benign	1.0	T
Sift4G	Benign	0.94	T
Polyphen		0.0020	B
Vest4		0.056
MPC		0.21
ClinPred		0.0013	T
GERP RS		0.27
Varity_R		0.049
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs6076347; hg19: chr20-25398790; COSMIC: COSV52465262; COSMIC: COSV52465262;