Genetic Variant NM_021067.5:c.247C>T (chr20-25418112-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PS3PP3PP5BP4

The NM_021067.5(GINS1):c.247C>T(p.Arg83Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00066 in 1,585,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000883274: "Well-established functional studies show a deleterious effect" (https://www.ncbi.nlm.nih.gov/pubmed/28414293)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 0 hom. )

Consequence

GINS1
NM_021067.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 5.07

Publications

9 publications found

Variant links:

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)

GINS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000883274: "Well-established functional studies show a deleterious effect" (https://www.ncbi.nlm.nih.gov/pubmed/28414293).; SCV001529939: This variant has been previously reported as compound heterozygous in three families with autosomal recessive growth retardation along with neutropenia and NK cell deficiency and was shown to impair GINS complex formation by functional study. PMID 28414293

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 20-25418112-C-T is Pathogenic according to our data. Variant chr20-25418112-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 487511.

BP4

Computational evidence support a benign effect (MetaRNN=0.1745882). . Strength limited to SUPPORTING due to the PP5.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GINS1	NM_021067.5	MANE Select	c.247C>T	p.Arg83Cys	missense	Exon 4 of 7	NP_066545.3
GINS1	NM_001410830.1		c.247C>T	p.Arg83Cys	missense	Exon 4 of 6	NP_001397759.1	A0A8Q3WLL7
GINS1	NM_001410831.1		c.76-7099C>T		intron	N/A	NP_001397760.1	A0A8Q3WLJ3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GINS1	ENST00000262460.5	TSL:1 MANE Select	c.247C>T	p.Arg83Cys	missense	Exon 4 of 7	ENSP00000262460.4	Q14691
GINS1	ENST00000696807.1		c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	ENSP00000512886.1	A0A8Q3WLL0
GINS1	ENST00000696810.1		c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	ENSP00000512888.1	A0A8Q3WLL0

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00434

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000887

AC:

223

AN:

251434

AF XY:

0.000890

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00439

Gnomad NFE exome

AF:

0.000994

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000663

AC:

951

AN:

1433612

Hom.:

Cov.:

AF XY:

0.000636

AC XY:

455

AN XY:

715052

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

33028

American (AMR)

AF:

0.000313

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00

AC:

AN:

85784

European-Finnish (FIN)

AF:

0.00391

AC:

209

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000640

AC:

695

AN:

1086000

Other (OTH)

AF:

0.000488

AC:

AN:

59452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000624

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41556

American (AMR)

AF:

0.000262

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00434

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000663

Hom.:

Bravo

AF:

0.000329

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000939

AC:

114

EpiCase

AF:

0.000818

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined immunodeficiency due to GINS1 deficiency (3)

not provided (3)

GINS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.17

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.2

PhyloP100

5.1

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.98

MPC

1.1

ClinPred

0.23

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.93

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over