rs80338890

Variant names:

• chr7-100621127-C-T
• rs80338890
• NM_003227.4:c.2137-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003227.4(TFR2):​c.2137-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,512,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TFR2 NM_003227.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.57
• Publications: 3 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-100621127-C-T is Pathogenic according to our data. Variant chr7-100621127-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21371.

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.2137-1G>A		splice_acceptor intron	N/A	NP_003218.2
	TFR2	NM_001206855.3		c.1624-1G>A		splice_acceptor intron	N/A	NP_001193784.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	ENST00000223051.8	TSL:1 MANE Select	c.2137-1G>A		splice_acceptor intron	N/A	ENSP00000223051.3
	TFR2	ENST00000855275.1		c.2233-1G>A		splice_acceptor intron	N/A	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.2230-1G>A		splice_acceptor intron	N/A	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000771 AC: 1 AN: 129684 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: 0.0000216

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 14 AN: 1360450 Hom.: 0 Cov.: 31 AF XY: 0.0000105 AC XY: 7 AN XY: 664324

African (AFR) AF: 0.00 AC: 0 AN: 31028

American (AMR) AF: 0.00 AC: 0 AN: 33980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23116

East Asian (EAS) AF: 0.00 AC: 0 AN: 35158

South Asian (SAS) AF: 0.00 AC: 0 AN: 74402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4190

European-Non Finnish (NFE) AF: 0.0000133 AC: 14 AN: 1054308

Other (OTH) AF: 0.00 AC: 0 AN: 56268

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Hemochromatosis type 3 (2)
-	1	-	Hereditary hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		7.6
GERP RS		5.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: -25
DS_AL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs80338890; hg19: chr7-100218750;