chr1-99717523-C-A

Variant names:

• chr1-99717523-C-A
• NM_001361041.2:c.1123G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001361041.2(FRRS1):​c.1123G>T​(p.Ala375Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRRS1 NM_001361041.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1123G>T	p.Ala375Ser	missense splice_region	Exon 11 of 17	NP_001347970.1	Q6ZNA5-1
	FRRS1	NM_001013660.4		c.1123G>T	p.Ala375Ser	missense splice_region	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.1123G>T	p.Ala375Ser	missense splice_region	Exon 11 of 17	ENSP00000496583.2	Q6ZNA5-1
	FRRS1	ENST00000287474.9	TSL:2	c.1123G>T	p.Ala375Ser	missense splice_region	Exon 11 of 17	ENSP00000287474.4	Q6ZNA5-2
	FRRS1	ENST00000852116.1		c.1123G>T	p.Ala375Ser	missense splice_region	Exon 10 of 16	ENSP00000522175.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

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	0.10
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0075	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.26
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.012	D
Polyphen		0.94	P
Vest4		0.37
MutPred		0.47		Gain of glycosylation at A375 (P = 0.0551)
MVP		0.55
MPC		0.29
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.27
gMVP		0.41
Mutation Taster		=70/30	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

hg19: chr1-100183079;