Genetic Variant TFR2:p.Ser383Arg (chr7-100631010-G-C) – 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.1149C>G(p.Ser383Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 1,371,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S383S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000066 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0860

Publications

1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

TFR2 links:

LOC124901709 (HGNC:):

LOC124901709 links:

Genome browser will be placed here

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=0.014428109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4 link	c.1149C>G	p.Ser383Arg	missense_variant	Exon 9 of 18	ENST00000223051.8	NP_003218.2	Q9UP52-1
TFR2	NM_001206855.3 link	c.636C>G	p.Ser212Arg	missense_variant	Exon 6 of 15		NP_001193784.1	Q9UP52-2
LOC124901709	XR_007060454.1 link	n.434-146G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.1149C>G	p.Ser383Arg	missense_variant	Exon 9 of 18	1	NM_003227.4	ENSP00000223051.3		Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152128

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000325

AC:

AN:

123224

AF XY:

0.0000155

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000189

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000656

AC:

AN:

1371664

Hom.:

Cov.:

AF XY:

0.00000742

AC XY:

AN XY:

673774

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31242

American (AMR)

AF:

0.000182

AC:

AN:

32972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21950

East Asian (EAS)

AF:

0.00

AC:

AN:

36478

South Asian (SAS)

AF:

0.00

AC:

AN:

69964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3982

European-Non Finnish (NFE)

AF:

0.00000279

AC:

AN:

1074302

Other (OTH)

AF:

0.00

AC:

AN:

57276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.581

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74304

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2088

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000894

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.0

(source)

DANN

Benign

0.95

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.44

M_CAP

Benign

0.0031

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.1

PhyloP100

0.086

PROVEAN

Benign

0.90

REVEL

Benign

0.028

Sift

Benign

0.13

Sift4G

Pathogenic

0.0

Vest4

0.35

MutPred

0.28

Loss of catalytic residue at P298 (P = 0.012);

MVP

0.24

ClinPred

0.035

GERP RS

-1.1

Varity_R

0.058

Mutation Taster

=297/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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7-100631010-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over