10-100152307-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (10029 hom., cov: 32)
  • Exomes 𝑓: 0.43 (148505 hom.)
• Consequence: ERLIN1 NM_006459.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.93

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERLIN1	NM_006459.4	c.871A>G	p.Ile291Val	missense_variant	11/11	ENST00000421367.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERLIN1	ENST00000421367.7	c.871A>G	p.Ile291Val	missense_variant	11/11	1	NM_006459.4	P1
ERLIN1	ENST00000407654.7	c.871A>G	p.Ile291Val	missense_variant	12/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48963 AN: 152068 Hom.: 10031 Cov.: 32

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

GnomAD3 exomes AF: 0.335 AC: 84196 AN: 251116 Hom.: 17313 AF XY: 0.339 AC XY: 46043 AN XY: 135718

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 SAS exome AF: 0.160

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.: 33 AF XY: 0.427 AC XY: 309690 AN XY: 726030

Gnomad4 AFR exome AF: 0.0767

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.347

Gnomad4 EAS exome AF: 0.0511

Gnomad4 SAS exome AF: 0.166

Gnomad4 FIN exome AF: 0.381

Gnomad4 NFE exome AF: 0.493

Gnomad4 OTH exome AF: 0.393

GnomAD4 genome AF: 0.322 AC: 48951 AN: 152186 Hom.: 10029 Cov.: 32 AF XY: 0.313 AC XY: 23317 AN XY: 74398

Gnomad4 AFR AF: 0.0970

Gnomad4 AMR AF: 0.321

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.0652

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.342

Alfa AF: 0.436 Hom.: 40253

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 62 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.15
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0011	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.0000040	P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.061
Sift	Benign	0.14	T;T
Sift4G	Benign	0.15	T;T
Vest4		0.21
MPC		0.019
ClinPred		0.017	T
GERP RS		4.4
gMVP		0.50

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

Other links and lift over

dbSNP: rs2862954; hg19: chr10-101912064; COSMIC: COSV64941107; COSMIC: COSV64941107;