20-25418154-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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
• Publications: 54 publications found

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]

GINS1 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to GINS1 deficiency

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021067.5. 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
	GINS1	NM_021067.5	MANE Select	c.289G>A	p.Val97Ile	missense	Exon 4 of 7	NP_066545.3
	GINS1	NM_001410830.1		c.289G>A	p.Val97Ile	missense	Exon 4 of 6	NP_001397759.1
	GINS1	NR_134574.2		n.437G>A		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GINS1	ENST00000262460.5	TSL:1 MANE Select	c.289G>A	p.Val97Ile	missense	Exon 4 of 7	ENSP00000262460.4
	GINS1	ENST00000696814.1		c.289G>A	p.Val97Ile	missense	Exon 4 of 8	ENSP00000512895.1
	GINS1	ENST00000696894.1		c.289G>A	p.Val97Ile	missense	Exon 4 of 7	ENSP00000512956.1

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

GnomAD2 exomes AF: 0.382 AC: 95925 AN: 251376 AF XY: 0.389

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 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

African (AFR) AF: 0.142 AC: 4716 AN: 33298

American (AMR) AF: 0.388 AC: 17364 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12777 AN: 26040

East Asian (EAS) AF: 0.00328 AC: 130 AN: 39676

South Asian (SAS) AF: 0.328 AC: 28205 AN: 85972

European-Finnish (FIN) AF: 0.425 AC: 22680 AN: 53354

Middle Eastern (MID) AF: 0.450 AC: 2582 AN: 5734

European-Non Finnish (NFE) AF: 0.475 AC: 521339 AN: 1098022

Other (OTH) AF: 0.413 AC: 24715 AN: 59894

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

African (AFR) AF: 0.154 AC: 6388 AN: 41484

American (AMR) AF: 0.382 AC: 5827 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1681 AN: 3472

East Asian (EAS) AF: 0.00887 AC: 46 AN: 5188

South Asian (SAS) AF: 0.313 AC: 1507 AN: 4820

European-Finnish (FIN) AF: 0.424 AC: 4472 AN: 10556

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32001 AN: 67980

Other (OTH) AF: 0.384 AC: 810 AN: 2112

Alfa AF: 0.433 Hom.: 74132

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 v4.9

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
PhyloP100		1.7
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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