rs387907053

Positions:

• chr11-124924890-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_152722.5(HEPACAM):​c.265G>A​(p.Gly89Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HEPACAM NM_152722.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 6.15

Genes affected

HEPACAM (HGNC:26361): (hepatic and glial cell adhesion molecule) The protein encoded by this gene is a single-pass type I membrane protein that localizes to the cytoplasmic side of the cell membrane. The encoded protein acts as a homodimer and is involved in cell motility and cell-matrix interactions. The expression of this gene is downregulated or undetectable in many cancer cell lines, so this may be a tumor suppressor gene. [provided by RefSeq, Jul 2011]

LOC107984406 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-124924890-C-T is Pathogenic according to our data. Variant chr11-124924890-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEPACAM	NM_152722.5	c.265G>A	p.Gly89Ser	missense_variant	2/7	ENST00000298251.5	NP_689935.2
LOC107984406	XR_001748429.3	n.335-18510C>T		intron_variant, non_coding_transcript_variant
HEPACAM	NM_001411043.1	c.265G>A	p.Gly89Ser	missense_variant	2/7		NP_001397972.1
HEPACAM	XM_005271449.3	c.265G>A	p.Gly89Ser	missense_variant	2/7		XP_005271506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEPACAM	ENST00000298251.5	c.265G>A	p.Gly89Ser	missense_variant	2/7	1	NM_152722.5	ENSP00000298251	P1
HEPACAM	ENST00000703807.1	c.265G>A	p.Gly89Ser	missense_variant	2/7			ENSP00000515485
HEPACAM	ENST00000526273.1	n.37G>A		non_coding_transcript_exon_variant	1/2	2
HEPACAM	ENST00000528971.1	n.671G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2023	Published functional studies demonstrate a damaging effect on protein function (Arnedo et al., 2014; Hoegg-Beiler et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31960914, 24647135, 20301707, 27535533, 21419380, 25044933) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HEPACAM function (PMID: 25044933). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 30919). This missense change has been observed in individual(s) with autosomal dominant megalencephalic leukoencephalopathy with subcortical cysts (PMID: 21419380). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 89 of the HEPACAM protein (p.Gly89Ser). -

Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.G89S in HEPACAM (NM_152722.5) has been previously reported as a de novo mutation in autosomal dominant megalencephalic leukoencephalopathy (Lopez-Hernandez T et al). Studies in HeLa cells demonstrate that G89S impacts the function of the HEPACAM protein (Arnedo et al, 2014). The variant has been submitted to ClinVar as Pathogenic. The p.G89S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico tools are contradictory in their predictions (SIFT-Tolerated, Polyphen-2-damaging) and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 08, 2011	- -

Megalencephalic leukoencephalopathy with subcortical cysts 2A Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Feb 10, 2021	This missense variant (c.265G>A, p.Gly89Ser) has not been observed in population databases (gnomAD). The change has been reported in the literature (PMID 21419380, PMID 25044933). Variant prediction programs indicate a deleterious effect on the protein, and this is supported by functional studies (PMID 21419380, PMID 25044933). -

HEPACAM-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2022

The HEPACAM c.265G>A variant is predicted to result in the amino acid substitution p.Gly89Ser. This variant has been reported in individuals with autosomal dominant megalencephalic leukoencephalopathy with subcortical cysts, and functional studies support its pathogenicity (López-Hernández et al. 2011. PubMed ID: 21419380; Arnedo et al. 2014. PubMed ID: 25044933; Elorza-Vidal et al 2020. PubMed ID: 31960914). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.31
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.55		Gain of phosphorylation at G89 (P = 0.1802);
MVP		0.56
MPC		1.0
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.70

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: rs387907053; hg19: chr11-124794786;