1-99709029-C-T

Variant names:

• chr1-99709029-C-T
• rs1571086972
• NM_001361041.2:c.1778G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.45

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]

ACMG classification

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
FRRS1	NM_001361041.2	c.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
FRRS1	ENST00000646001.2	c.1778G>A	p.Ter593Ter	stop_retained_variant	Exon 17 of 17		NM_001361041.2	ENSP00000496583.2
FRRS1	ENST00000287474.9	c.1750G>A	p.Glu584Lys	missense_variant	Exon 17 of 17	2		ENSP00000287474.4

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

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

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

Other links and lift over

dbSNP: rs1571086972; hg19: chr1-100174585;