8-41539774-G-A

Variant names:

• chr8-41539774-G-A
• rs1806804302
• NM_032336.3:c.394G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032336.3(GINS4):​c.394G>A​(p.Glu132Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GINS4 NM_032336.3 missense, splice_region
• Scores: Splicing: ADA: 0.0004323
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58
• Publications: 0 publications found

Genes affected

GINS4 (HGNC:28226): (GINS complex subunit 4) The yeast heterotetrameric GINS complex is made up of Sld5, Psf1 (GINS1; MIM 610608), 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]). See GINS1 for additional information about the GINS complex.[supplied by OMIM, Mar 2008]

GPAT4-AS1 (HGNC:55539): (GPAT4 and GINS4 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032336.3. 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
	GINS4	NM_032336.3	MANE Select	c.394G>A	p.Glu132Lys	missense splice_region	Exon 5 of 8	NP_115712.1	Q9BRT9-1
	GPAT4-AS1	NR_125824.1		n.64-2464C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GINS4	ENST00000276533.4	TSL:1 MANE Select	c.394G>A	p.Glu132Lys	missense splice_region	Exon 5 of 8	ENSP00000276533.3	Q9BRT9-1
	GINS4	ENST00000518671.5	TSL:3	c.394G>A	p.Glu132Lys	missense splice_region	Exon 5 of 8	ENSP00000428754.1	Q9BRT9-1
	GINS4	ENST00000523277.6	TSL:5	c.394G>A	p.Glu132Lys	missense splice_region	Exon 5 of 7	ENSP00000428901.1	E5RFF9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459766 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726378

African (AFR) AF: 0.0000299 AC: 1 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110204

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.16	T
Polyphen		0.78	P
Vest4		0.70
MutPred		0.55		Gain of methylation at E132 (P = 0.0024)
MVP		0.45
MPC		0.30
ClinPred		0.95	D
GERP RS		0.15
Varity_R		0.70
gMVP		0.46
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.066
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

Other links and lift over

dbSNP: rs1806804302; hg19: chr8-41397293;