1-99717486-A-G

Variant names:

• chr1-99717486-A-G
• rs866097624
• NM_001361041.2:c.1160T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001361041.2(FRRS1):​c.1160T>C​(p.Ile387Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FRRS1 NM_001361041.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26672274).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001361041.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRRS1	NM_001361041.2	MANE Select	c.1160T>C	p.Ile387Thr	missense	Exon 11 of 17	NP_001347970.1	Q6ZNA5-1
	FRRS1	NM_001013660.4		c.1160T>C	p.Ile387Thr	missense	Exon 11 of 17	NP_001013682.2	Q6ZNA5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRRS1	ENST00000646001.2	MANE Select	c.1160T>C	p.Ile387Thr	missense	Exon 11 of 17	ENSP00000496583.2	Q6ZNA5-1
	FRRS1	ENST00000287474.9	TSL:2	c.1160T>C	p.Ile387Thr	missense	Exon 11 of 17	ENSP00000287474.4	Q6ZNA5-2
	FRRS1	ENST00000852116.1		c.1160T>C	p.Ile387Thr	missense	Exon 10 of 16	ENSP00000522175.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461704 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727162

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000268340), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.83
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.8
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.045
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.016	B
Vest4		0.40
MutPred		0.47		Loss of stability (P = 0.0038)
MVP		0.37
MPC		0.071
ClinPred		0.43	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.43
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs866097624; hg19: chr1-100183042;