11-124919932-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000408930.7(HEPN1):c.182A>T(p.His61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0857 in 1,613,728 control chromosomes in the GnomAD database, including 6,429 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 0.074 ( 435 hom., cov: 31)

Exomes 𝑓: 0.087 ( 5994 hom. )

Consequence

HEPN1
ENST00000408930.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0890

Publications

17 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: 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

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=0.0018495321).

BP6

Variant 11-124919932-A-T is Benign according to our data. Variant chr11-124919932-A-T is described in ClinVar as Benign. ClinVar VariationId is 303297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEPACAM	NM_152722.5 link	c.*1206T>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000298251.5	NP_689935.2	Q14CZ8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEPN1	ENST00000408930.7 link	c.182A>T	p.His61Leu	missense_variant	Exon 1 of 1	6		ENSP00000386143.4		Q6WQI6
HEPACAM	ENST00000298251.5 link	c.*1206T>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_152722.5	ENSP00000298251.4		Q14CZ8-1

Frequencies

GnomAD3 genomes

AF:

0.0739

AC:

11235

AN:

151946

Hom.:

437

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0588

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.0502

Gnomad ASJ

AF:

0.0375

Gnomad EAS

AF:

0.0253

Gnomad SAS

AF:

0.0711

Gnomad FIN

AF:

0.0605

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0963

Gnomad OTH

AF:

0.0603

GnomAD2 exomes

AF:

0.0685

AC:

16922

AN:

247136

AF XY:

0.0707

show subpopulations

Gnomad AFR exome

AF:

0.0580

Gnomad AMR exome

AF:

0.0306

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.0286

Gnomad FIN exome

AF:

0.0663

Gnomad NFE exome

AF:

0.0905

Gnomad OTH exome

AF:

0.0600

GnomAD4 exome

AF:

0.0870

AC:

127137

AN:

1461664

Hom.:

5994

Cov.:

AF XY:

0.0870

AC XY:

63255

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0543

AC:

1817

AN:

33474

American (AMR)

AF:

0.0323

AC:

1444

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

921

AN:

26136

East Asian (EAS)

AF:

0.0244

AC:

968

AN:

39700

South Asian (SAS)

AF:

0.0745

AC:

6425

AN:

86244

European-Finnish (FIN)

AF:

0.0669

AC:

3573

AN:

53420

Middle Eastern (MID)

AF:

0.0515

AC:

291

AN:

5648

European-Non Finnish (NFE)

AF:

0.0958

AC:

106555

AN:

1111944

Other (OTH)

AF:

0.0852

AC:

5143

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

6656

13312

19967

26623

33279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3818

7636

11454

15272

19090

<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:

0.0739

AC:

11232

AN:

152064

Hom.:

435

Cov.:

AF XY:

0.0711

AC XY:

5289

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0587

AC:

2436

AN:

41486

American (AMR)

AF:

0.0501

AC:

766

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0375

AC:

130

AN:

3468

East Asian (EAS)

AF:

0.0254

AC:

131

AN:

5166

South Asian (SAS)

AF:

0.0716

AC:

344

AN:

4806

European-Finnish (FIN)

AF:

0.0605

AC:

640

AN:

10582

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0962

AC:

6539

AN:

67956

Other (OTH)

AF:

0.0597

AC:

126

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

549

1097

1646

2194

2743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<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:

0.0856

Hom.:

482

Bravo

AF:

0.0698

TwinsUK

AF:

0.101

AC:

374

ALSPAC

AF:

0.0944

AC:

364

ESP6500AA

AF:

0.0588

AC:

225

ESP6500EA

AF:

0.0879

AC:

728

ExAC

AF:

0.0709

AC:

8570

Asia WGS

AF:

0.0440

AC:

154

AN:

3478

EpiCase

AF:

0.0944

EpiControl

AF:

0.0845

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Megalencephalic leukoencephalopathy with subcortical cysts

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.086

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.15

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.031

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0038

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

PhyloP100

0.089

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.33

REVEL

Benign

0.048

Sift4G

Benign

0.83

Polyphen

0.0

Vest4

0.028

MPC

0.043

ClinPred

0.0016

GERP RS

-3.4

Varity_R

0.096

gMVP

0.0040

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over