rs387907053
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G89A) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
HEPACAM
NM_152722.5 missense
NM_152722.5 missense
Scores
4
10
5
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_152722.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr11-124924889-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30920.Status of the report is criteria_provided_single_submitter, 1 stars.
PP5
?
Variant 11-124924890-C-T is Pathogenic according to our data. Variant chr11-124924890-C-T is described in ClinVar as [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 | UniProt |
---|---|---|---|---|---|---|---|
HEPACAM | NM_152722.5 | c.265G>A | p.Gly89Ser | missense_variant | 2/7 | ENST00000298251.5 | |
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 | ||
HEPACAM | XM_005271449.3 | c.265G>A | p.Gly89Ser | missense_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEPACAM | ENST00000298251.5 | c.265G>A | p.Gly89Ser | missense_variant | 2/7 | 1 | NM_152722.5 | P1 | |
HEPACAM | ENST00000703807.1 | c.265G>A | p.Gly89Ser | missense_variant | 2/7 | ||||
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
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 exome
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5
AN:
1461888
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31
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4
AN XY:
727244
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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). - |
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) - |
Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 08, 2011 | - - |
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. - |
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. - |
Megalencephalic leukoencephalopathy with subcortical cysts 2A Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of phosphorylation at G89 (P = 0.1802);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at