rs2862954

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006459.4(ERLIN1):c.871A>G(p.Ile291Val) variant causes a missense change. The variant allele was found at a frequency of 0.422 in 1,611,308 control chromosomes in the GnomAD database, including 158,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I291F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.32 ( 10029 hom., cov: 32)

Exomes 𝑓: 0.43 ( 148505 hom. )

Consequence

ERLIN1
NM_006459.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.93

Publications

59 publications found

Variant links:

Genes affected

ERLIN1 (HGNC:16947): (ER lipid raft associated 1) The protein encoded by this gene is part of a protein complex that mediates degradation of inositol 1,4,5-trisphosphate receptors in the endoplasmic reticulum. The encoded protein also binds cholesterol and regulates the SREBP signaling pathway, which promotes cellular cholesterol homeostasis. Defects in this gene have been associated with spastic paraplegia 62. [provided by RefSeq, Dec 2016]

ERLIN1 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 62
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ERLIN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010764897).

BP6

Variant 10-100152307-T-C is Benign according to our data. Variant chr10-100152307-T-C is described in ClinVar as Benign. ClinVar VariationId is 1167054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006459.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERLIN1	NM_006459.4	MANE Select	c.871A>G	p.Ile291Val	missense	Exon 11 of 11	NP_006450.2	O75477
ERLIN1	NM_001100626.2		c.871A>G	p.Ile291Val	missense	Exon 12 of 12	NP_001094096.1	O75477
ERLIN1	NM_001347857.2		c.871A>G	p.Ile291Val	missense	Exon 12 of 12	NP_001334786.1	O75477

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERLIN1	ENST00000421367.7	TSL:1 MANE Select	c.871A>G	p.Ile291Val	missense	Exon 11 of 11	ENSP00000410964.2	O75477
ERLIN1	ENST00000407654.7	TSL:1	c.871A>G	p.Ile291Val	missense	Exon 12 of 12	ENSP00000384900.3	O75477
ERLIN1	ENST00000971770.1		c.745A>G	p.Ile249Val	missense	Exon 10 of 10	ENSP00000641829.1

Frequencies

GnomAD3 genomes

AF:

0.322

AC:

48963

AN:

152068

Hom.:

10031

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0973

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.322

Gnomad ASJ

AF:

0.348

Gnomad EAS

AF:

0.0656

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.369

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.479

Gnomad OTH

AF:

0.341

GnomAD2 exomes

AF:

0.335

AC:

84196

AN:

251116

AF XY:

0.339

show subpopulations

Gnomad AFR exome

AF:

0.0874

Gnomad AMR exome

AF:

0.247

Gnomad ASJ exome

AF:

0.348

Gnomad EAS exome

AF:

0.0609

Gnomad FIN exome

AF:

0.377

Gnomad NFE exome

AF:

0.478

Gnomad OTH exome

AF:

0.381

GnomAD4 exome

AF:

0.433

AC:

631454

AN:

1459122

Hom.:

148505

Cov.:

AF XY:

0.427

AC XY:

309690

AN XY:

726030

show subpopulations

African (AFR)

AF:

0.0767

AC:

2566

AN:

33470

American (AMR)

AF:

0.255

AC:

11395

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.347

AC:

9065

AN:

26116

East Asian (EAS)

AF:

0.0511

AC:

2029

AN:

39696

South Asian (SAS)

AF:

0.166

AC:

14268

AN:

86210

European-Finnish (FIN)

AF:

0.381

AC:

20326

AN:

53402

Middle Eastern (MID)

AF:

0.274

AC:

1580

AN:

5766

European-Non Finnish (NFE)

AF:

0.493

AC:

546564

AN:

1109460

Other (OTH)

AF:

0.393

AC:

23661

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

17034

34068

51101

68135

85169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15460

30920

46380

61840

77300

<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:

0.322

AC:

48951

AN:

152186

Hom.:

10029

Cov.:

AF XY:

0.313

AC XY:

23317

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0970

AC:

4030

AN:

41538

American (AMR)

AF:

0.321

AC:

4907

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

1208

AN:

3470

East Asian (EAS)

AF:

0.0652

AC:

338

AN:

5186

South Asian (SAS)

AF:

0.165

AC:

796

AN:

4820

European-Finnish (FIN)

AF:

0.369

AC:

3907

AN:

10578

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.479

AC:

32543

AN:

67990

Other (OTH)

AF:

0.342

AC:

720

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1527

3053

4580

6106

7633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<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:

0.419

Hom.:

54373

Bravo

AF:

0.309

TwinsUK

AF:

0.505

AC:

1872

ALSPAC

AF:

0.496

AC:

1913

ESP6500AA

AF:

0.104

AC:

460

ESP6500EA

AF:

0.470

AC:

4044

ExAC

AF:

0.332

AC:

40348

Asia WGS

AF:

0.117

AC:

411

AN:

3478

EpiCase

AF:

0.469

EpiControl

AF:

0.475

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 62 (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.15

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0011

MetaSVM

Benign

-0.95

PhyloP100

5.9

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.79

REVEL

Benign

0.061

Sift

Benign

0.14

Sift4G

Benign

0.15

Vest4

0.21

MPC

0.019

ClinPred

0.017

GERP RS

4.4

gMVP

0.50

Mutation Taster

=98/2

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over