5-172935197-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001031711.3(ERGIC1):c.652G>A(p.Ala218Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,613,936 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 14 hom. )

Consequence

ERGIC1
NM_001031711.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 9.60

Publications

9 publications found

Variant links:

Genes affected

ERGIC1 (HGNC:29205): (endoplasmic reticulum-golgi intermediate compartment 1) This gene encodes a cycling membrane protein which is an endoplasmic reticulum-golgi intermediate compartment (ERGIC) protein which interacts with other members of this protein family to increase their turnover. [provided by RefSeq, Jul 2008]

ERGIC1 Gene-Disease associations (from GenCC):

arthrogryposis multiplex congenita 2, neurogenic type
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ERGIC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015652359).

BP6

Variant 5-172935197-G-A is Benign according to our data. Variant chr5-172935197-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2656081.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERGIC1	NM_001031711.3 link	c.652G>A	p.Ala218Thr	missense_variant	Exon 9 of 10	ENST00000393784.8	NP_001026881.1	Q969X5-1
ERGIC1	XM_011534597.2 link	c.724G>A	p.Ala242Thr	missense_variant	Exon 9 of 10		XP_011532899.1
ERGIC1	XM_047417411.1 link	c.376G>A	p.Ala126Thr	missense_variant	Exon 6 of 7		XP_047273367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERGIC1	ENST00000393784.8 link	c.652G>A	p.Ala218Thr	missense_variant	Exon 9 of 10	1	NM_001031711.3	ENSP00000377374.3		Q969X5-1

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00220

AC:

554

AN:

251444

AF XY:

0.00208

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00605

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00315

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00251

AC:

3665

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1771

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00136

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00670

AC:

175

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000893

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00210

AC:

112

AN:

53388

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00276

AC:

3069

AN:

1112002

Other (OTH)

AF:

0.00230

AC:

139

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

204

408

612

816

1020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00218

AC:

331

AN:

152086

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000579

AC:

AN:

41468

American (AMR)

AF:

0.00295

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00750

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00104

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00299

AC:

203

AN:

68004

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00285

Hom.:

Bravo

AF:

0.00221

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00210

AC:

255

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ERGIC1: BP4, BS2 -

ERGIC1-related disorder

Benign:1

Aug 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.031

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0054

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

9.6

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.46

REVEL

Benign

0.18

Sift

Benign

0.87

Sift4G

Benign

0.36

Polyphen

0.084

Vest4

0.82

MVP

0.29

MPC

0.66

ClinPred

0.067

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

gMVP

0.77

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over