Genetic Variant GINS3:p.Met214Thr (chr16-58404719-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022770.4(GINS3):c.641T>C(p.Met214Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GINS3
NM_022770.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.08

Variant links:

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]

GINS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.074361295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GINS3	NM_022770.4 link	c.641T>C	p.Met214Thr	missense_variant	Exon 3 of 3	ENST00000318129.6	NP_073607.2	Q9BRX5-1A0A0S2Z5L0
GINS3	NM_001126129.2 link	c.758T>C	p.Met253Thr	missense_variant	Exon 4 of 4		NP_001119601.1	Q9BRX5-3A0A0S2Z5P2
GINS3	NM_001126130.2 link	c.407T>C	p.Met136Thr	missense_variant	Exon 2 of 2		NP_001119602.1	Q9BRX5-2A0A0S2Z5L4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GINS3	ENST00000318129.6 link	c.641T>C	p.Met214Thr	missense_variant	Exon 3 of 3	1	NM_022770.4	ENSP00000318196.6	Q9BRX5-1
GINS3	ENST00000426538.6 link	c.758T>C	p.Met253Thr	missense_variant	Exon 4 of 4	1		ENSP00000401018.2	Q9BRX5-3
GINS3	ENST00000328514.11 link	c.407T>C	p.Met136Thr	missense_variant	Exon 2 of 2	1		ENSP00000327449.7	Q9BRX5-2
GINS3	ENST00000567143.1 link	n.1778T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250300

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135312

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460742

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726696

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.758T>C (p.M253T) alteration is located in exon 4 (coding exon 4) of the GINS3 gene. This alteration results from a T to C substitution at nucleotide position 758, causing the methionine (M) at amino acid position 253 to be replaced by a threonine (T). 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

0.090

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.058

.;.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.020

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.51

T;T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.074

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.1

.;.;L

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.6

D;N;N

REVEL

Benign

0.054

Sift

Uncertain

0.013

D;D;D

Sift4G

Uncertain

0.038

D;D;T

Polyphen

0.0010, 0.0

.;B;B

Vest4

0.15

MVP

0.33

MPC

0.34

ClinPred

0.45

GERP RS

5.1

Varity_R

0.25

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over