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11-94045866-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001098672.2(HEPHL1):c.364C>T(p.Arg122Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

HEPHL1
NM_001098672.2 stop_gained

Scores

2
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.80
Variant links:
Genes affected
HEPHL1 (HGNC:30477): (hephaestin like 1) Enables ferroxidase activity. Involved in cellular iron ion homeostasis. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 11-94045866-C-T is Pathogenic according to our data. Variant chr11-94045866-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1678388.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HEPHL1NM_001098672.2 linkuse as main transcriptc.364C>T p.Arg122Ter stop_gained 2/20 ENST00000315765.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HEPHL1ENST00000315765.10 linkuse as main transcriptc.364C>T p.Arg122Ter stop_gained 2/205 NM_001098672.2 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000197
AC:
30
AN:
152062
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000507
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000763
AC:
19
AN:
249146
Hom.:
0
AF XY:
0.0000888
AC XY:
12
AN XY:
135158
show subpopulations
Gnomad AFR exome
AF:
0.000517
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000531
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.0000759
AC:
111
AN:
1461572
Hom.:
0
Cov.:
31
AF XY:
0.0000825
AC XY:
60
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000657
Gnomad4 OTH exome
AF:
0.000331
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000197
AC:
30
AN:
152062
Hom.:
0
Cov.:
31
AF XY:
0.000189
AC XY:
14
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.000507
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000139
Hom.:
0
Bravo
AF:
0.000185
ESP6500AA
AF:
0.000532
AC:
2
ESP6500EA
AF:
0.000122
AC:
1
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000745
AC:
9
EpiCase
AF:
0.000218
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsApr 28, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.62
Cadd
Pathogenic
37
Dann
Uncertain
1.0
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.89
D
MutationTaster
Benign
1.0
A
Vest4
0.15
GERP RS
4.0

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.

Other links and lift over

dbSNP: rs200703100; hg19: chr11-93779032; COSMIC: COSV59889707; API