chr1-99712514-T-C

Variant names:

• chr1-99712514-T-C
• rs755854673
• NM_001361041.2:c.1325A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001361041.2(FRRS1):​c.1325A>G​(p.His442Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,583,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: FRRS1 NM_001361041.2 missense, splice_region
• Scores: Splicing: ADA: 0.0002320
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0770
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07384282).
• BP6: Variant 1-99712514-T-C is Benign according to our data. Variant chr1-99712514-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3851793.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1325A>G	p.His442Arg	missense splice_region	Exon 13 of 17	NP_001347970.1	Q6ZNA5-1
	FRRS1	NM_001013660.4		c.1325A>G	p.His442Arg	missense splice_region	Exon 13 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.1325A>G	p.His442Arg	missense splice_region	Exon 13 of 17	ENSP00000496583.2	Q6ZNA5-1
	FRRS1	ENST00000287474.9	TSL:2	c.1325A>G	p.His442Arg	missense splice_region	Exon 13 of 17	ENSP00000287474.4	Q6ZNA5-2
	FRRS1	ENST00000852116.1		c.1325A>G	p.His442Arg	missense splice_region	Exon 12 of 16	ENSP00000522175.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000878 AC: 2 AN: 227908 AF XY: 0.0000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000273 AC: 39 AN: 1431054 Hom.: 0 Cov.: 27 AF XY: 0.0000225 AC XY: 16 AN XY: 711992

African (AFR) AF: 0.00 AC: 0 AN: 32094

American (AMR) AF: 0.00 AC: 0 AN: 38044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 81156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.0000328 AC: 36 AN: 1097142

Other (OTH) AF: 0.0000506 AC: 3 AN: 59248

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.062
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.95
DANN	Benign	0.14
DEOGEN2	Benign	0.0097	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.72	N
PhyloP100		0.077
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.34
Sift	Benign	0.69	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.55		Gain of MoRF binding (P = 0.1272)
MVP		0.30
MPC		0.064
ClinPred		0.0098	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.24
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
dbscSNV1_RF	Benign	0.14
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

Other links and lift over

dbSNP: rs755854673; hg19: chr1-100178070;