Variant X-66170736-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001367233.3(HEPH):c.166A>G(p.Ile56Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,091,914 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000023 ( 0 hom. 14 hem. )

Consequence

HEPH
NM_001367233.3 missense, splice_region

Scores

Splicing: ADA: 0.9646

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01

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 Likely_benign. Variant got -3 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS2

High Hemizygotes in GnomAdExome4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEPH	NM_001367233.3 linkuse as main transcript	c.166A>G	p.Ile56Val	missense_variant, splice_region_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.166A>G	p.Ile56Val	missense_variant, splice_region_variant	2/21	1	NM_001367233.3	P5	Q9BQS7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000344

AC:

AN:

174201

Hom.:

AF XY:

0.0000336

AC XY:

AN XY:

59527

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1091914

Hom.:

Cov.:

AF XY:

0.0000391

AC XY:

AN XY:

357686

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000206

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000955

Gnomad4 OTH exome

AF:

0.0000436

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Oct 13, 2023

The c.328A>G (p.I110V) alteration is located in exon 2 (coding exon 2) of the HEPH gene. This alteration results from a A to G substitution at nucleotide position 328, causing the isoleucine (I) at amino acid position 110 to be replaced by a valine (V). 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

0.063

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.95

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.48

T;T;T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.092

T;T;T;T;T;T

MetaSVM

Uncertain

0.31

MutationTaster

Benign

1.0

D;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.32

N;N;N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.27

T;T;T;T;T;T

Sift4G

Benign

0.42

T;T;T;T;T;T

Polyphen

0.0, 0.0020

.;.;.;B;B;.

Vest4

0.080

MutPred

0.39

.;Gain of sheet (P = 0.0266);.;.;Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);

MVP

0.73

MPC

0.070

ClinPred

0.017

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.10

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.010

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