16-58403137-C-G

Variant names:

• chr16-58403137-C-G
• NM_022770.4:c.226C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022770.4(GINS3):​c.226C>G​(p.Leu76Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GINS3 NM_022770.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

Genes affected

GINS3 (HGNC:25851): (GINS complex subunit 3) This gene encodes a protein subunit of the GINS heterotetrameric complex, which is essential for the initiation of DNA replication and replisome progression in eukaryotes. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GINS3	NM_022770.4	c.226C>G	p.Leu76Val	missense_variant	Exon 2 of 3	ENST00000318129.6	NP_073607.2
GINS3	NM_001126129.2	c.343C>G	p.Leu115Val	missense_variant	Exon 3 of 4		NP_001119601.1
GINS3	NM_001126130.2	c.187-1362C>G		intron_variant	Intron 1 of 1		NP_001119602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GINS3	ENST00000318129.6	c.226C>G	p.Leu76Val	missense_variant	Exon 2 of 3	1	NM_022770.4	ENSP00000318196.6
GINS3	ENST00000426538.6	c.343C>G	p.Leu115Val	missense_variant	Exon 3 of 4	1		ENSP00000401018.2
GINS3	ENST00000328514.11	c.187-1362C>G		intron_variant	Intron 1 of 1	1		ENSP00000327449.7
GINS3	ENST00000567143.1	n.196C>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.343C>G (p.L115V) alteration is located in exon 3 (coding exon 3) of the GINS3 gene. This alteration results from a C to G substitution at nucleotide position 343, causing the leucine (L) at amino acid position 115 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.3	.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.051	T;T
Polyphen		0.98	.;D
Vest4		0.80
MutPred		0.95		.;Gain of MoRF binding (P = 0.0773);
MVP		0.31
MPC		0.98
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.78
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-58437041; COSMIC: COSV58919192;