rs387907053

Variant names:

• chr11-124924890-C-T
• rs387907053
• NM_152722.5:c.265G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PM5 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 (★★). ClinVar reports functional evidence for this variant: "SCV002820285: Studies in HeLa cells demonstrate that G89S impacts the function of the HEPACAM protein (Arnedo et al, 2014)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G89R) has been classified as 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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• megalencephalic leukoencephalopathy with subcortical cysts 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• macrocephaly-autism syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• megalencephalic leukoencephalopathy with subcortical cysts

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000254943 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002820285: Studies in HeLa cells demonstrate that G89S impacts the function of the HEPACAM protein (Arnedo et al, 2014).; SCV005187419: "Variant prediction programs indicate a deleterious effect on the protein, and this is supported by functional studies" (PMID 21419380, PMID 25044933).; SCV000329992: Published functional studies demonstrate a damaging effect on protein function (PMID: 25044933, 24647135); SCV002240335: Experimental studies have shown that this missense change affects HEPACAM function (PMID: 25044933).; SCV004115068: "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)."
• 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 chr11-124924890-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 4531823.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/Likely_pathogenic. ClinVar VariationId is 30919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152722.5. 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
	HEPACAM	NM_152722.5	MANE Select	c.265G>A	p.Gly89Ser	missense	Exon 2 of 7	NP_689935.2	Q14CZ8-1
	HEPACAM	NM_001411043.1		c.265G>A	p.Gly89Ser	missense	Exon 2 of 7	NP_001397972.1	A0A994J4I1
	HEPACAM	NM_001441320.1		c.265G>A	p.Gly89Ser	missense	Exon 2 of 7	NP_001428249.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPACAM	ENST00000298251.5	TSL:1 MANE Select	c.265G>A	p.Gly89Ser	missense	Exon 2 of 7	ENSP00000298251.4	Q14CZ8-1
	HEPACAM	ENST00000872129.1		c.265G>A	p.Gly89Ser	missense	Exon 2 of 7	ENSP00000542188.1
	HEPACAM	ENST00000703807.1		c.265G>A	p.Gly89Ser	missense	Exon 2 of 7	ENSP00000515485.1	A0A994J4I1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability (2)
2	-	-	not provided (2)
1	-	-	HEPACAM-related disorder (1)
1	-	-	Megalencephalic leukoencephalopathy with subcortical cysts 2A (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.1
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
Mutation Taster		=28/72	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907053; hg19: chr11-124794786;