1-99709029-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001013660.4(FRRS1):​c.1750G>A​(p.Glu584Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

FRRS1
NM_001013660.4 missense

Scores

2
3
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.45
Variant links:
Genes affected
FRRS1 (HGNC:27622): (ferric chelate reductase 1) Members of the cytochrome b561 (CYB561; MIM 600019) family, including FRRS1, reduce ferric to ferrous iron before its transport from the endosome to the cytoplasm (Vargas et al., 2003 [PubMed 14499595]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10785928).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FRRS1NM_001361041.2 linkc.1778G>A p.Ter593Ter stop_retained_variant Exon 17 of 17 ENST00000646001.2 NP_001347970.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FRRS1ENST00000646001.2 linkc.1778G>A p.Ter593Ter stop_retained_variant Exon 17 of 17 NM_001361041.2 ENSP00000496583.2 Q6ZNA5-1
FRRS1ENST00000287474.9 linkc.1750G>A p.Glu584Lys missense_variant Exon 17 of 17 2 ENSP00000287474.4 Q6ZNA5-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1461784
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
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:
0.0000126
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000487
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 21, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1750G>A (p.E584K) alteration is located in exon 17 (coding exon 15) of the FRRS1 gene. This alteration results from a G to A substitution at nucleotide position 1750, causing the glutamic acid (E) at amino acid position 584 to be replaced by a lysine (K). 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
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
13
DANN
Uncertain
1.0
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.092
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.45
T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.96
T
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.16
N
REVEL
Benign
0.065
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.0080
B
Vest4
0.29
MutPred
0.36
Gain of methylation at E584 (P = 0.02);
MVP
0.41
MPC
0.34
ClinPred
0.99
D
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs1571086972; hg19: chr1-100174585; API