Genetic Variant TFR2:p.His33Asn (chr7-100641165-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003227.4(TFR2):c.97C>A(p.His33Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H33Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.0460

Publications

4 publications found

Variant links:

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

TFR2 links:

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ACMG classification

Classification was made for transcript

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=0.06542876).

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.97C>A	p.His33Asn	missense	Exon 2 of 18	NP_003218.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFR2	ENST00000223051.8	TSL:1 MANE Select	c.97C>A	p.His33Asn	missense	Exon 2 of 18	ENSP00000223051.3	Q9UP52-1
TFR2	ENST00000855275.1		c.136C>A	p.His46Asn	missense	Exon 3 of 20	ENSP00000525334.1
TFR2	ENST00000855257.1		c.97C>A	p.His33Asn	missense	Exon 3 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1378838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678086

African (AFR)

AF:

0.00

AC:

AN:

31248

American (AMR)

AF:

0.00

AC:

AN:

31208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22812

East Asian (EAS)

AF:

0.00

AC:

AN:

36770

South Asian (SAS)

AF:

0.00

AC:

AN:

75284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070054

Other (OTH)

AF:

0.00

AC:

AN:

57136

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hemochromatosis type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.6

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.16

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.62

M_CAP

Benign

0.0039

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.046

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.058

Sift

Benign

0.11

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.14

MutPred

0.11

Gain of relative solvent accessibility (P = 0.0166)

MVP

0.33

MPC

0.36

ClinPred

0.10

GERP RS

-4.0

PromoterAI

0.34

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.071

gMVP

0.24

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over