rs369355407

chr7-100621017-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003227.4(TFR2):c.2246G>A(p.Arg749Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,601,626 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 (★). Synonymous variant affecting the same amino acid position (i.e. R749R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.715

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10374743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFR2	NM_003227.4	c.2246G>A	p.Arg749Gln	missense_variant	18/18	ENST00000223051.8
TFR2	NM_001206855.3	c.1733G>A	p.Arg578Gln	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.2246G>A	p.Arg749Gln	missense_variant	18/18	1	NM_003227.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152202 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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1449424 Hom.: 0 Cov.: 31 AF XY: 0.00000972 AC XY: 7 AN XY: 720012

Gnomad4 AFR exome AF: 0.0000603

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000354

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000994

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000391 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemochromatosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2021

This sequence change replaces arginine with glutamine at codon 749 of the TFR2 protein (p.Arg749Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs369355407, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with TFR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 219806). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.086	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.68	T;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.11	N;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.055
Sift	Benign	0.43	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.12	B;B
Vest4		0.071
MVP		0.41
MPC		0.38
ClinPred		0.11	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs369355407; hg19: chr7-100218640;