Variant X-66170711-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001367233.3(HEPH):c.141C>G(p.Ile47Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 1,207,977 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

HEPH
NM_001367233.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.815

Variant links:

Genes affected

HEPH (HGNC:4866): (hephaestin) This gene encodes a member of the multicopper oxidase protein family. The encoded protein is involved in the transport of dietary iron from epithelial cells of the intestinal lumen into the circulatory system, and may be involved in copper transport and homeostasis. In mouse, defects in this gene can lead to severe microcytic anemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

HEPH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEPH	NM_001367233.3 linkuse as main transcript	c.141C>G	p.Ile47Met	missense_variant	2/21	ENST00000343002.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEPH	ENST00000343002.7 linkuse as main transcript	c.141C>G	p.Ile47Met	missense_variant	2/21	1	NM_001367233.3	P5	Q9BQS7-1

Frequencies

GnomAD3 genomes

AF:

0.0000358

AC:

AN:

111793

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33951

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000168

AC:

AN:

178815

Hom.:

AF XY:

0.00

AC XY:

AN XY:

63771

show subpopulations

Gnomad AFR exome

AF:

0.000233

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1096184

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361738

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000358

AC:

AN:

111793

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33951

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.303C>G (p.I101M) alteration is located in exon 2 (coding exon 2) of the HEPH gene. This alteration results from a C to G substitution at nucleotide position 303, causing the isoleucine (I) at amino acid position 101 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

0.98

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D;D;D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.62

D;D;D;D;D;D

MetaSVM

Pathogenic

0.85

MutationTaster

Benign

1.0

D;N;N;N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.9

N;N;N;N;N;N

REVEL

Pathogenic

0.75

Sift

Uncertain

0.012

D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D

Polyphen

0.96, 0.85

.;.;.;D;P;.

Vest4

0.46

MVP

0.51

MPC

0.39

ClinPred

0.45

GERP RS

3.2

Varity_R

0.39

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over