rs80338888

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM4PP5_Very_Strong

The NM_003227.4(TFR2):c.1861_1872delGCCGTGGCCCAG(p.Ala621_Gln624del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000834 in 1,559,462 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A621A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

TFR2
NM_003227.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 7.17

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: 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: Pathogenic. The variant received 10 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_003227.4.

PP5

Variant 7-100627386-GCTGGGCCACGGC-G is Pathogenic according to our data. Variant chr7-100627386-GCTGGGCCACGGC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TFR2	NM_003227.4 link	c.1861_1872delGCCGTGGCCCAG	p.Ala621_Gln624del	conservative_inframe_deletion	Exon 16 of 18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3 link	c.1348_1359delGCCGTGGCCCAG	p.Ala450_Gln453del	conservative_inframe_deletion	Exon 13 of 15		NP_001193784.1
LOC124901709	XR_007060454.1 link	n.434-3757_434-3746delCTGGGCCACGGC		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.1861_1872delGCCGTGGCCCAG	p.Ala621_Gln624del	conservative_inframe_deletion	Exon 16 of 18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

166580

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000711

AC:

AN:

1407252

Hom.:

AF XY:

0.00000576

AC XY:

AN XY:

694998

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000311

AC:

AN:

32138

American (AMR)

AF:

0.00

AC:

AN:

36136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25234

East Asian (EAS)

AF:

0.00

AC:

AN:

36608

South Asian (SAS)

AF:

0.00

AC:

AN:

80092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49478

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00000646

AC:

AN:

1083560

Other (OTH)

AF:

0.0000171

AC:

AN:

58350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000264076), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.380

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 11, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 07, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary hemochromatosis

Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1861_1872del, results in the deletion of 4 amino acid(s) of the TFR2 protein (p.Ala621_Gln624del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs80338888, gnomAD 0.004%). This variant has been observed in individuals with hereditary hemochromatosis (PMID: 11984516, 12809944, 26408288). It has also been observed to segregate with disease in related individuals. This variant is also known as AVAQ 594-597 del. Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TFR2 function (PMID: 18094142, 26408288). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.2

Mutation Taster

=42/158

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over