chr10-100183802-C-A

Variant names:

• chr10-100183802-C-A
• rs876661322
• NM_006459.4:c.149G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006459.4(ERLIN1):​c.149G>T​(p.Gly50Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERLIN1 NM_006459.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 10-100183802-C-A is Pathogenic according to our data. Variant chr10-100183802-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 226427.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERLIN1	NM_006459.4	MANE Select	c.149G>T	p.Gly50Val	missense	Exon 2 of 11	NP_006450.2	O75477
	ERLIN1	NM_001100626.2		c.149G>T	p.Gly50Val	missense	Exon 3 of 12	NP_001094096.1	O75477
	ERLIN1	NM_001347857.2		c.149G>T	p.Gly50Val	missense	Exon 3 of 12	NP_001334786.1	O75477

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERLIN1	ENST00000421367.7	TSL:1 MANE Select	c.149G>T	p.Gly50Val	missense	Exon 2 of 11	ENSP00000410964.2	O75477
	ERLIN1	ENST00000407654.7	TSL:1	c.149G>T	p.Gly50Val	missense	Exon 3 of 12	ENSP00000384900.3	O75477
	ERLIN1	ENST00000971770.1		c.149G>T	p.Gly50Val	missense	Exon 2 of 10	ENSP00000641829.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary spastic paraplegia 62 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
MutPred		0.85		Loss of disorder (P = 0.0201)
MVP		0.98
MPC		0.52
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876661322; hg19: chr10-101943559;