X-66189731-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001367233.3(HEPH):c.856G>A(p.Ala286Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,097,607 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: not found (cov: 22)
Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )
Consequence
HEPH
NM_001367233.3 missense
NM_001367233.3 missense
Scores
2
5
8
Clinical Significance
Conservation
PhyloP100: 1.61
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]
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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 | c.856G>A | p.Ala286Thr | missense_variant | 6/21 | ENST00000343002.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEPH | ENST00000343002.7 | c.856G>A | p.Ala286Thr | missense_variant | 6/21 | 1 | NM_001367233.3 | P5 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
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22
GnomAD3 exomes AF: 0.0000164 AC: 3AN: 183289Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67755
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GnomAD4 exome AF: 0.00000547 AC: 6AN: 1097607Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1AN XY: 362961
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GnomAD4 genome Cov.: 22
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22
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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 | Sep 16, 2021 | The c.1018G>A (p.A340T) alteration is located in exon 6 (coding exon 6) of the HEPH gene. This alteration results from a G to A substitution at nucleotide position 1018, causing the alanine (A) at amino acid position 340 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationTaster
Benign
N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
0.27, 0.76
.;.;.;B;P;.
Vest4
MutPred
0.44
.;.;.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at