rs387907054

Variant names:

• chr11-124924889-C-G
• rs387907054
• NM_152722.5:c.266G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-124924889-C-G
• chr11-124924889-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_152722.5(HEPACAM):​c.266G>C​(p.Gly89Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G89S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEPACAM NM_152722.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88
• Publications: 0 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: Ambry Genetics, ClinGen, 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: Likely_pathogenic. The variant received 7 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 chr11-124924890-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEPACAM	NM_152722.5	c.266G>C	p.Gly89Ala	missense_variant	Exon 2 of 7	ENST00000298251.5	NP_689935.2
HEPACAM	NM_001411043.1	c.266G>C	p.Gly89Ala	missense_variant	Exon 2 of 7		NP_001397972.1
HEPACAM	NM_001441320.1	c.266G>C	p.Gly89Ala	missense_variant	Exon 2 of 7		NP_001428249.1
LOC107984406	XR_001748429.3	n.335-18511C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEPACAM	ENST00000298251.5	c.266G>C	p.Gly89Ala	missense_variant	Exon 2 of 7	1	NM_152722.5	ENSP00000298251.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 08, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.34
Sift	Benign	0.082	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.57		Gain of sheet (P = 0.1945);
MVP		0.52
MPC		0.98
ClinPred		0.90	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.77
Mutation Taster		=13/87	disease causing

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: rs387907054; hg19: chr11-124794785;