Variant X-66189818-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001367233.3(HEPH):c.943A>G(p.Thr315Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,208,408 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000022 ( 0 hom. 6 hem. )

Consequence

HEPH
NM_001367233.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23664075).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEPH	NM_001367233.3 linkuse as main transcript	c.943A>G	p.Thr315Ala	missense_variant	6/21	ENST00000343002.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEPH	ENST00000343002.7 linkuse as main transcript	c.943A>G	p.Thr315Ala	missense_variant	6/21	1	NM_001367233.3	P5	Q9BQS7-1

Frequencies

GnomAD3 genomes

AF:

0.0000541

AC:

AN:

110844

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

33054

show subpopulations

Gnomad AFR

AF:

0.0000658

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:

0.0000754

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000220

AC:

AN:

181945

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

66489

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000494

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1097564

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

362948

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000285

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000541

AC:

AN:

110844

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

33054

show subpopulations

Gnomad4 AFR

AF:

0.0000658

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:

0.0000754

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000577

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

Apr 19, 2023

The c.1105A>G (p.T369A) alteration is located in exon 6 (coding exon 6) of the HEPH gene. This alteration results from a A to G substitution at nucleotide position 1105, causing the threonine (T) at amino acid position 369 to be replaced by an alanine (A). 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

0.074

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.20

CADD

Benign

7.2

DANN

Benign

0.23

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.75

T;T;T;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.24

T;T;T;T;T;T

MetaSVM

Uncertain

0.69

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.79

N;N;N;N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.52

T;T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;T;T

Polyphen

0.0070, 0.0040

.;.;.;B;B;.

Vest4

0.34

MutPred

0.46

.;.;.;.;Loss of glycosylation at T315 (P = 0.0299);Loss of glycosylation at T315 (P = 0.0299);

MVP

0.55

MPC

0.084

ClinPred

0.45

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.087

gMVP

0.72

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

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