11-124920666-A-C

Position:

• chr11-124920666-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_152722.5(HEPACAM):​c.*472T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000558 in 765,000 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: HEPACAM NM_152722.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0930

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-124920666-A-C is Benign according to our data. Variant chr11-124920666-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 303303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0013 (160/122786) while in subpopulation AMR AF= 0.00303 (31/10236). AF 95% confidence interval is 0.00229. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEPN1	NM_001037558.4	c.*649A>C		3_prime_UTR_variant	1/1	ENST00000408930.7	NP_001032647.2
HEPACAM	NM_152722.5	c.*472T>G		3_prime_UTR_variant	7/7	ENST00000298251.5	NP_689935.2
LOC107984406	XR_001748429.3	n.335-22734A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEPACAM	ENST00000298251.5	c.*472T>G		3_prime_UTR_variant	7/7	1	NM_152722.5	ENSP00000298251	P1
HEPN1	ENST00000408930.7	c.*649A>C		3_prime_UTR_variant	1/1		NM_001037558.4	ENSP00000386143	P1
HEPACAM	ENST00000703807.1	c.*472T>G		3_prime_UTR_variant	7/7			ENSP00000515485

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 159 AN: 122712 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00303

Gnomad ASJ AF: 0.00184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00249

GnomAD4 exome AF: 0.000416 AC: 267 AN: 642214 Hom.: 1 Cov.: 8 AF XY: 0.000420 AC XY: 125 AN XY: 297830

Gnomad4 AFR exome AF: 0.00424

Gnomad4 AMR exome AF: 0.00464

Gnomad4 ASJ exome AF: 0.00113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00130 AC: 160 AN: 122786 Hom.: 0 Cov.: 25 AF XY: 0.00130 AC XY: 75 AN XY: 57598

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.00303

Gnomad4 ASJ AF: 0.00184

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00247

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00158

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.5
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs372662415; hg19: chr11-124790562;