rs974304393

Variant names:

• chr20-25407773-C-G
• rs974304393
• NM_021067.5:c.-48C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021067.5(GINS1):​c.-48C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000392 in 1,276,616 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: GINS1 NM_021067.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.0590
• Publications: 1 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)

LOC105372581 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GINS1	NM_021067.5	MANE Select	c.-48C>G		5_prime_UTR	Exon 1 of 7	NP_066545.3
	GINS1	NM_001410830.1		c.-48C>G		5_prime_UTR	Exon 1 of 6	NP_001397759.1	A0A8Q3WLL7
	GINS1	NM_001410831.1		c.-48C>G		5_prime_UTR	Exon 1 of 4	NP_001397760.1	A0A8Q3WLJ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GINS1	ENST00000262460.5	TSL:1 MANE Select	c.-48C>G		5_prime_UTR	Exon 1 of 7	ENSP00000262460.4	Q14691
	GINS1	ENST00000696814.1		c.-48C>G		5_prime_UTR	Exon 1 of 8	ENSP00000512895.1	A0A8Q3WMM5
	GINS1	ENST00000696894.1		c.-48C>G		5_prime_UTR	Exon 1 of 7	ENSP00000512956.1	A0A8Q3SJ10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242728 AF XY: 0.00000759

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000918

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000392 AC: 5 AN: 1276616 Hom.: 0 Cov.: 18 AF XY: 0.00000620 AC XY: 4 AN XY: 644924

African (AFR) AF: 0.00 AC: 0 AN: 29928

American (AMR) AF: 0.00 AC: 0 AN: 44130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24844

East Asian (EAS) AF: 0.00 AC: 0 AN: 38594

South Asian (SAS) AF: 0.00 AC: 0 AN: 82028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5442

European-Non Finnish (NFE) AF: 0.00000529 AC: 5 AN: 944504

Other (OTH) AF: 0.00 AC: 0 AN: 54268

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Combined immunodeficiency due to GINS1 deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	19
DANN	Benign	0.63
PhyloP100		0.059
PromoterAI		0.21	Neutral
Mutation Taster		=76/224	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: 0

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

Other links and lift over

dbSNP: rs974304393; hg19: chr20-25388409;