rs387907055

Positions:

• chr11-124924881-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_152722.5(HEPACAM):​c.274C>T​(p.Arg92Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEPACAM NM_152722.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.51

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]

HEPACAM (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 11-124924881-G-A is Pathogenic according to our data. Variant chr11-124924881-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30921.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.274C>T	p.Arg92Trp	missense_variant	2/7	ENST00000298251.5	NP_689935.2
HEPACAM	NM_001411043.1	c.274C>T	p.Arg92Trp	missense_variant	2/7		NP_001397972.1
HEPACAM	XM_005271449.3	c.274C>T	p.Arg92Trp	missense_variant	2/7		XP_005271506.1
LOC107984406	XR_001748429.3	n.335-18519G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEPACAM	ENST00000298251.5	c.274C>T	p.Arg92Trp	missense_variant	2/7	1	NM_152722.5	ENSP00000298251.4
HEPACAM	ENST00000703807.1	c.274C>T	p.Arg92Trp	missense_variant	2/7			ENSP00000515485.1
HEPACAM	ENST00000526273.1	n.46C>T		non_coding_transcript_exon_variant	1/2	2
HEPACAM	ENST00000528971.1	n.680C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Jul 14, 2023	This sequence variant is a single nucleotide substitution (C>T) at position 274 of the coding sequence of the HEPACAM gene that results in an arginine to tryptophan amino acid change at residue 92 of the hepatic and glial cell adhesion molecule protein. This residue falls in a domain required for proper homo-oligomerization (PMID: 31960914). This is a previously reported variant (ClinVar 30921) that has been observed in individuals affected by megalencephalic leukoencephalopathy, autism, and other HEPACAM-related disorders (PMID: 31372844, 21419380, 28191890, 26402605, 27322623, 25363768); it is often seen as a de novo variant. This variant is absent from the gnomAD population database (0/~282000 alleles). Multiple bioinformatic tools predict that this arginine to tryptophan amino acid change would be damaging, and the Arg92 residue at this position is highly conserved across the vertebrate species examined. Several functiol studies suggest impaired homo-oligomerization, decreased plasma membrane localization, and impaired function of the variant protein (PMID: 21419380, 31960914, 28905383, 27819278, 23793458, 34531445, 21624973, 22405205, 25044933); additiolly, in a mouse model the variant protein caused white matter vacuolization and other abnormalities (PMID: 31372844). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PM5, PP3, PS3, PS4 -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HEPACAM function (PMID: 21419380, 31372844). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HEPACAM protein function. ClinVar contains an entry for this variant (Variation ID: 30921). This missense change has been observed in individual(s) with autosomal dominant megalencephalic leukoencephalopathy with subcortical cysts (PMID: 21419380, 31372844). 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 92 of the HEPACAM protein (p.Arg92Trp). -

Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 08, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.62		Loss of phosphorylation at T90 (P = 0.0744);
MVP		0.67
MPC		1.1
ClinPred		0.99	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.88

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: rs387907055; hg19: chr11-124794777; COSMIC: COSV100005427; COSMIC: COSV100005427;