11-124919859-T-C

Position:

chr11-124919859-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001037558.4(HEPN1):c.109T>C(p.Trp37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.725 in 1,613,796 control chromosomes in the GnomAD database, including 427,053 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.76 ( 44820 hom., cov: 31)

Exomes 𝑓: 0.72 ( 382233 hom. )

Consequence

HEPN1
NM_001037558.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.357

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 links:

LOC107984406 (HGNC:):

LOC107984406 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2734231E-6).

BP6

Variant 11-124919859-T-C is Benign according to our data. Variant chr11-124919859-T-C is described in ClinVar as [Benign]. Clinvar id is 303295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HEPN1	NM_001037558.4 linkuse as main transcript	c.109T>C	p.Trp37Arg	missense_variant	1/1	ENST00000408930.7	NP_001032647.2
HEPACAM	NM_152722.5 linkuse as main transcript	c.*1279A>G		3_prime_UTR_variant	7/7	ENST00000298251.5	NP_689935.2
LOC107984406	XR_001748429.3 linkuse as main transcript	n.335-23541T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEPN1	ENST00000408930.7 linkuse as main transcript	c.109T>C	p.Trp37Arg	missense_variant	1/1		NM_001037558.4	ENSP00000386143	P1
HEPACAM	ENST00000298251.5 linkuse as main transcript	c.*1279A>G		3_prime_UTR_variant	7/7	1	NM_152722.5	ENSP00000298251	P1	Q14CZ8-1
HEPACAM	ENST00000703807.1 linkuse as main transcript	c.*1279A>G		3_prime_UTR_variant	7/7			ENSP00000515485

Frequencies

GnomAD3 genomes

AF:

0.763

AC:

115979

AN:

152008

Hom.:

44772

Cov.:

show subpopulations

Gnomad AFR

AF:

0.862

Gnomad AMI

AF:

0.654

Gnomad AMR

AF:

0.682

Gnomad ASJ

AF:

0.634

Gnomad EAS

AF:

0.914

Gnomad SAS

AF:

0.755

Gnomad FIN

AF:

0.794

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.713

Gnomad OTH

AF:

0.752

GnomAD3 exomes

AF:

0.731

AC:

180501

AN:

247062

Hom.:

66870

AF XY:

0.731

AC XY:

98113

AN XY:

134266

show subpopulations

Gnomad AFR exome

AF:

0.868

Gnomad AMR exome

AF:

0.617

Gnomad ASJ exome

AF:

0.632

Gnomad EAS exome

AF:

0.912

Gnomad SAS exome

AF:

0.752

Gnomad FIN exome

AF:

0.778

Gnomad NFE exome

AF:

0.712

Gnomad OTH exome

AF:

0.711

GnomAD4 exome

AF:

0.721

AC:

1054057

AN:

1461672

Hom.:

382233

Cov.:

AF XY:

0.722

AC XY:

524983

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.866

Gnomad4 AMR exome

AF:

0.624

Gnomad4 ASJ exome

AF:

0.631

Gnomad4 EAS exome

AF:

0.920

Gnomad4 SAS exome

AF:

0.750

Gnomad4 FIN exome

AF:

0.774

Gnomad4 NFE exome

AF:

0.710

Gnomad4 OTH exome

AF:

0.732

GnomAD4 genome

AF:

0.763

AC:

116084

AN:

152124

Hom.:

44820

Cov.:

AF XY:

0.767

AC XY:

57065

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.862

Gnomad4 AMR

AF:

0.682

Gnomad4 ASJ

AF:

0.634

Gnomad4 EAS

AF:

0.914

Gnomad4 SAS

AF:

0.756

Gnomad4 FIN

AF:

0.794

Gnomad4 NFE

AF:

0.714

Gnomad4 OTH

AF:

0.754

Alfa

AF:

0.720

Hom.:

97359

Bravo

AF:

0.758

TwinsUK

AF:

0.731

AC:

2711

ALSPAC

AF:

0.712

AC:

2744

ESP6500AA

AF:

0.869

AC:

3438

ESP6500EA

AF:

0.700

AC:

5822

ExAC

AF:

0.737

AC:

89045

Asia WGS

AF:

0.850

AC:

2956

AN:

3478

EpiCase

AF:

0.709

EpiControl

AF:

0.704

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Megalencephalic leukoencephalopathy with subcortical cysts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.075

DANN

Benign

0.44

DEOGEN2

Benign

0.0072

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0000013

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.20

PROVEAN

Benign

1.4

REVEL

Benign

0.098

Sift4G

Benign

0.49

Polyphen

0.0

Vest4

0.015

MutPred

0.14

Gain of disorder (P = 0.0023);

MPC

0.055

ClinPred

0.000029

GERP RS

0.86

Varity_R

0.094

gMVP

0.0039

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over