rs80338888

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong

The NM_003227.4(TFR2):c.1861_1872del(p.Ala621_Gln624del) variant causes a 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. Variant has been reported in ClinVar as 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 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 7.17

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 links:

LOC124901709 (HGNC:):

LOC124901709 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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]. Clinvar id is 21370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100627386-GCTGGGCCACGGC-G is described in Lovd as [Pathogenic]. Variant chr7-100627386-GCTGGGCCACGGC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TFR2	NM_003227.4 linkuse as main transcript	c.1861_1872del	p.Ala621_Gln624del	inframe_deletion	16/18	ENST00000223051.8
LOC124901709	XR_007060454.1 linkuse as main transcript	n.434-3757_434-3746del		intron_variant, non_coding_transcript_variant
TFR2	NM_001206855.3 linkuse as main transcript	c.1348_1359del	p.Ala450_Gln453del	inframe_deletion	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8 linkuse as main transcript	c.1861_1872del	p.Ala621_Gln624del	inframe_deletion	16/18	1	NM_003227.4	P1	Q9UP52-1

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

GnomAD4 exome

AF:

0.00000711

AC:

AN:

1407252

Hom.:

AF XY:

0.00000576

AC XY:

AN XY:

694998

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000646

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hereditary hemochromatosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

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 protein 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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over