rs202221581

Variant names:

• chr7-100631041-C-T
• rs202221581
• NM_003227.4:c.1118G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-100631041-C-T
• chr7-100631041-C-A

Variant summary

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

The NM_003227.4(TFR2):​c.1118G>A​(p.Gly373Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000263 in 1,583,602 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G373R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 5.37
• Publications: 9 publications found

Genes affected

TFR2 (HGNC:11762): (transferrin receptor 2) This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

TFR2 Gene-Disease associations (from GenCC):

• hemochromatosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia

LOC124901709 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003227.4. 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
	TFR2	NM_003227.4	MANE Select	c.1118G>A	p.Gly373Asp	missense	Exon 9 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.605G>A	p.Gly202Asp	missense	Exon 6 of 15	NP_001193784.1	Q9UP52-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	ENST00000223051.8	TSL:1 MANE Select	c.1118G>A	p.Gly373Asp	missense	Exon 9 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.1214G>A	p.Gly405Asp	missense	Exon 11 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.1118G>A	p.Gly373Asp	missense	Exon 10 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000353

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000320 AC: 68 AN: 212322 AF XY: 0.000241

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.000565

Gnomad OTH exome AF: 0.000397

GnomAD4 exome AF: 0.000268 AC: 383 AN: 1431364 Hom.: 1 Cov.: 31 AF XY: 0.000257 AC XY: 183 AN XY: 711194

African (AFR) AF: 0.0000629 AC: 2 AN: 31806

American (AMR) AF: 0.000482 AC: 18 AN: 37330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24202

East Asian (EAS) AF: 0.00 AC: 0 AN: 39400

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82494

European-Finnish (FIN) AF: 0.000135 AC: 7 AN: 51984

Middle Eastern (MID) AF: 0.000607 AC: 3 AN: 4944

European-Non Finnish (NFE) AF: 0.000307 AC: 338 AN: 1100298

Other (OTH) AF: 0.000238 AC: 14 AN: 58906

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74426

African (AFR) AF: 0.0000241 AC: 1 AN: 41544

American (AMR) AF: 0.000392 AC: 6 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68010

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000410 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000322 AC: 39

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hemochromatosis type 3 (3)
-	2	-	not provided (2)
-	1	-	Hemochromatosis type 1 (1)
-	1	-	Hereditary hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		5.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.060	T
Polyphen		1.0	D
Vest4		0.87
MVP		0.82
MPC		1.2
ClinPred		0.86	D
GERP RS		4.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.73
gMVP		0.90
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs202221581; hg19: chr7-100228664;