11-124919932-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001037558.4(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. 14/19 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 NM_001037558.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890

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]

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]

LOC107984406 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 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 id is 303297.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
HEPN1	NM_001037558.4	c.182A>T	p.His61Leu	missense_variant	1/1	ENST00000408930.7
HEPACAM	NM_152722.5	c.*1206T>A		3_prime_UTR_variant	7/7	ENST00000298251.5
LOC107984406	XR_001748429.3	n.335-23468A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEPN1	ENST00000408930.7	c.182A>T	p.His61Leu	missense_variant	1/1		NM_001037558.4	P1
HEPACAM	ENST00000298251.5	c.*1206T>A		3_prime_UTR_variant	7/7	1	NM_152722.5	P1
HEPACAM	ENST00000703807.1	c.*1206T>A		3_prime_UTR_variant	7/7

Frequencies

GnomAD3 genomes AF: 0.0739 AC: 11235 AN: 151946 Hom.: 437 Cov.: 31

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

GnomAD3 exomes AF: 0.0685 AC: 16922 AN: 247136 Hom.: 692 AF XY: 0.0707 AC XY: 9491 AN XY: 134300

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 SAS exome AF: 0.0741

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.: 34 AF XY: 0.0870 AC XY: 63255 AN XY: 727134

Gnomad4 AFR exome AF: 0.0543

Gnomad4 AMR exome AF: 0.0323

Gnomad4 ASJ exome AF: 0.0352

Gnomad4 EAS exome AF: 0.0244

Gnomad4 SAS exome AF: 0.0745

Gnomad4 FIN exome AF: 0.0669

Gnomad4 NFE exome AF: 0.0958

Gnomad4 OTH exome AF: 0.0852

GnomAD4 genome AF: 0.0739 AC: 11232 AN: 152064 Hom.: 435 Cov.: 31 AF XY: 0.0711 AC XY: 5289 AN XY: 74336

Gnomad4 AFR AF: 0.0587

Gnomad4 AMR AF: 0.0501

Gnomad4 ASJ AF: 0.0375

Gnomad4 EAS AF: 0.0254

Gnomad4 SAS AF: 0.0716

Gnomad4 FIN AF: 0.0605

Gnomad4 NFE AF: 0.0962

Gnomad4 OTH AF: 0.0597

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.086
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.15
Dann	Benign	0.60
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0038	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.048
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.043
ClinPred		0.0016	T
GERP RS		-3.4
Varity_R		0.096
gMVP		0.0040

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

Other links and lift over

dbSNP: rs78859654; hg19: chr11-124789828; COSMIC: COSV53431910; COSMIC: COSV53431910;