NM_001037558.4:c.109T>A

Variant names:

• chr11-124919859-T-A
• rs3802904
• NM_001037558.4:c.109T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001037558.4(HEPN1):​c.109T>A​(p.Trp37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HEPN1 NM_001037558.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.357
• Publications: 25 publications found

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]

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

ENSG00000254943 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03794402).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPN1	NM_001037558.4	MANE Select	c.109T>A	p.Trp37Arg	missense	Exon 1 of 1	NP_001032647.2	Q6WQI6
	HEPACAM	NM_152722.5	MANE Select	c.*1279A>T		3_prime_UTR	Exon 7 of 7	NP_689935.2	Q14CZ8-1
	HEPACAM	NM_001411043.1		c.*1279A>T		3_prime_UTR	Exon 7 of 7	NP_001397972.1	A0A994J4I1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPN1	ENST00000408930.7	TSL:6 MANE Select	c.109T>A	p.Trp37Arg	missense	Exon 1 of 1	ENSP00000386143.4	Q6WQI6
	HEPACAM	ENST00000298251.5	TSL:1 MANE Select	c.*1279A>T		3_prime_UTR	Exon 7 of 7	ENSP00000298251.4	Q14CZ8-1
	HEPACAM	ENST00000703807.1		c.*1279A>T		3_prime_UTR	Exon 7 of 7	ENSP00000515485.1	A0A994J4I1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 179002

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.060
DANN	Benign	0.53
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.36
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.13
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.14		Gain of disorder (P = 0.0023)
MVP		0.081
MPC		0.055
ClinPred		0.030	T
GERP RS		0.86
Varity_R		0.094
gMVP		0.0039
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs3802904; hg19: chr11-124789755;