Genetic Variant HEPN1:p.Trp37Gly (chr11-124919859-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001037558.4(HEPN1):c.109T>G(p.Trp37Gly) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W37R) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Consequence

HEPN1
NM_001037558.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.357

Publications

25 publications found

Variant links:

Genes affected

HEPN1 (HGNC:34400): (hepatocellular carcinoma, down-regulated 1) This gene is expressed predominantly in the liver. Transient transfection studies show the expression of this gene significantly inhibits cell growth, suggesting a role for this gene in apoptosis. Expression of this gene is down-regulated or lost in hepatocellular carcinomas (HCC), suggesting that loss of this gene is involved in carcinogenesis of hepatocytes (PMID:12971969). This gene maps to the 3'-noncoding region of the HEPACAM gene (GeneID:220296) on the antisense strand. [provided by RefSeq, Aug 2020]

HEPN1 links:

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

HEPACAM links:

ENSG00000254943 (HGNC:):

ENSG00000254943 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05749789).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037558.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEPN1	NM_001037558.4	MANE Select	c.109T>G	p.Trp37Gly	missense	Exon 1 of 1	NP_001032647.2	Q6WQI6
HEPACAM	NM_152722.5	MANE Select	c.*1279A>C		3_prime_UTR	Exon 7 of 7	NP_689935.2	Q14CZ8-1
HEPACAM	NM_001411043.1		c.*1279A>C		3_prime_UTR	Exon 7 of 7	NP_001397972.1	A0A994J4I1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEPN1	ENST00000408930.7	TSL:6 MANE Select	c.109T>G	p.Trp37Gly	missense	Exon 1 of 1	ENSP00000386143.4	Q6WQI6
HEPACAM	ENST00000298251.5	TSL:1 MANE Select	c.*1279A>C		3_prime_UTR	Exon 7 of 7	ENSP00000298251.4	Q14CZ8-1
HEPACAM	ENST00000703807.1		c.*1279A>C		3_prime_UTR	Exon 7 of 7	ENSP00000515485.1	A0A994J4I1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.25

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.029

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.15

M_CAP

Benign

0.024

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.95

PhyloP100

-0.36

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.9

REVEL

Benign

0.074

Sift4G

Benign

0.28

Polyphen

0.0020

Vest4

0.13

MutPred

0.39

Gain of disorder (P = 0.0036)

MVP

0.030

MPC

0.055

ClinPred

0.021

GERP RS

0.86

Varity_R

0.31

gMVP

0.0051

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over