Genetic Variant NM_016570.3:c.214A>G (chr12-29370115-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016570.3(ERGIC2):c.214A>G(p.Ser72Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000399 in 1,503,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

ERGIC2
NM_016570.3 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

Variant links:

Genes affected

ERGIC2 (HGNC:30208): (ERGIC and golgi 2) ERGIC2, or PTX1, is a ubiquitously expressed nuclear protein that is downregulated in prostate carcinoma (Kwok et al., 2001 [PubMed 11445006]).[supplied by OMIM, Aug 2008]

ERGIC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERGIC2	NM_016570.3 link	c.214A>G	p.Ser72Gly	missense_variant, splice_region_variant	Exon 3 of 14	ENST00000360150.9	NP_057654.2	Q96RQ1A0A024RB08Q86TD3
ERGIC2	XM_024449009.2 link	c.214A>G	p.Ser72Gly	missense_variant, splice_region_variant	Exon 3 of 14		XP_024304777.1
ERGIC2	XR_001748741.3 link	n.309A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERGIC2	ENST00000360150.9 link	c.214A>G	p.Ser72Gly	missense_variant, splice_region_variant	Exon 3 of 14	1	NM_016570.3	ENSP00000353270.4		Q96RQ1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

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:

0.00

GnomAD3 exomes

AF:

0.0000909

AC:

AN:

165032

Hom.:

AF XY:

0.000130

AC XY:

AN XY:

92374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00183

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000422

AC:

AN:

1351354

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

669292

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00179

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000103

Gnomad4 OTH exome

AF:

0.000108

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000226

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000124

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.214A>G (p.S72G) alteration is located in exon 3 (coding exon 2) of the ERGIC2 gene. This alteration results from a A to G substitution at nucleotide position 214, causing the serine (S) at amino acid position 72 to be replaced by a glycine (G). 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

0.11

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

T;T;T;.;T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Benign

0.0029

MetaRNN

Benign

0.17

T;T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.6

L;.;.;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.9

N;.;N;D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0040

D;.;D;D;D;D

Sift4G

Uncertain

0.044

D;D;D;.;.;.

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.70

MVP

0.79

MPC

0.19

ClinPred

0.29

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

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