11-124919859-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

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>C	p.Trp37Arg	missense	Exon 1 of 1	NP_001032647.2	Q6WQI6
HEPACAM	NM_152722.5	MANE Select	c.*1279A>G		3_prime_UTR	Exon 7 of 7	NP_689935.2	Q14CZ8-1
HEPACAM	NM_001411043.1		c.*1279A>G		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>C	p.Trp37Arg	missense	Exon 1 of 1	ENSP00000386143.4	Q6WQI6
HEPACAM	ENST00000298251.5	TSL:1 MANE Select	c.*1279A>G		3_prime_UTR	Exon 7 of 7	ENSP00000298251.4	Q14CZ8-1
HEPACAM	ENST00000703807.1		c.*1279A>G		3_prime_UTR	Exon 7 of 7	ENSP00000515485.1	A0A994J4I1

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

GnomAD2 exomes

AF:

0.731

AC:

180501

AN:

247062

AF XY:

0.731

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 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

African (AFR)

AF:

0.866

AC:

28998

AN:

33478

American (AMR)

AF:

0.624

AC:

27907

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.631

AC:

16502

AN:

26132

East Asian (EAS)

AF:

0.920

AC:

36512

AN:

39700

South Asian (SAS)

AF:

0.750

AC:

64686

AN:

86250

European-Finnish (FIN)

AF:

0.774

AC:

41372

AN:

53420

Middle Eastern (MID)

AF:

0.742

AC:

4266

AN:

5750

European-Non Finnish (NFE)

AF:

0.710

AC:

789626

AN:

1111836

Other (OTH)

AF:

0.732

AC:

44188

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

17247

34495

51742

68990

86237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19866

39732

59598

79464

99330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.763

AC:

116084

AN:

152124

Hom.:

44820

Cov.:

AF XY:

0.767

AC XY:

57065

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.862

AC:

35763

AN:

41482

American (AMR)

AF:

0.682

AC:

10430

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.634

AC:

2198

AN:

3468

East Asian (EAS)

AF:

0.914

AC:

4721

AN:

5166

South Asian (SAS)

AF:

0.756

AC:

3634

AN:

4810

European-Finnish (FIN)

AF:

0.794

AC:

8408

AN:

10592

Middle Eastern (MID)

AF:

0.762

AC:

224

AN:

294

European-Non Finnish (NFE)

AF:

0.714

AC:

48516

AN:

67996

Other (OTH)

AF:

0.754

AC:

1595

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1372

2744

4116

5488

6860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

854

1708

2562

3416

4270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.725

Hom.:

179002

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Megalencephalic leukoencephalopathy with subcortical cysts (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.075

(source)

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

PhyloP100

-0.36

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

Mutation Taster

=99/1

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over