1-99717523-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRRS1	NM_001361041.2	c.1123G>T	p.Ala375Ser	missense_variant, splice_region_variant	Exon 11 of 17	ENST00000646001.2	NP_001347970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRRS1	ENST00000646001.2	c.1123G>T	p.Ala375Ser	missense_variant, splice_region_variant	Exon 11 of 17		NM_001361041.2	ENSP00000496583.2
FRRS1	ENST00000287474.9	c.1123G>T	p.Ala375Ser	missense_variant, splice_region_variant	Exon 11 of 17	2		ENSP00000287474.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1123G>T (p.A375S) alteration is located in exon 11 (coding exon 9) of the FRRS1 gene. This alteration results from a G to T substitution at nucleotide position 1123, causing the alanine (A) at amino acid position 375 to be replaced by a serine (S). 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
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;T
M_CAP	Benign	0.0075	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.1	M;M
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);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-100183079;