rs80338888

Variant names:

• chr7-100627386-GCTGGGCCACGGC-G
• rs80338888
• NM_003227.4:c.1861_1872delGCCGTGGCCCAG

Your query was ambiguous. Multiple possible variants found:

• chr7-100627386-GCTGGGCCACGGC-G
• chr7-100627386-GCTGGGCCACGGC-GCTGGGCCACGGCCTGGGCCACGGC

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM4 PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV001591907: Experimental studies have shown that this variant affects TFR2 function (PMID:18094142, 26408288).". 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.17
• Publications: 4 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia

LOC124901709 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001591907: Experimental studies have shown that this variant affects TFR2 function (PMID: 18094142, 26408288).
• 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.

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.1861_1872delGCCGTGGCCCAG	p.Ala621_Gln624del	conservative_inframe_deletion	Exon 16 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.1348_1359delGCCGTGGCCCAG	p.Ala450_Gln453del	conservative_inframe_deletion	Exon 13 of 15	NP_001193784.1	Q9UP52-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	ENST00000223051.8	TSL:1 MANE Select	c.1861_1872delGCCGTGGCCCAG	p.Ala621_Gln624del	conservative_inframe_deletion	Exon 16 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.1957_1968delGCCGTGGCCCAG	p.Ala653_Gln656del	conservative_inframe_deletion	Exon 18 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.1861_1872delGCCGTGGCCCAG	p.Ala621_Gln624del	conservative_inframe_deletion	Exon 17 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33

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: 0 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: 10 AN: 1407252 Hom.: 0 AF XY: 0.00000576 AC XY: 4 AN XY: 694998

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

African (AFR) AF: 0.0000311 AC: 1 AN: 32138

American (AMR) AF: 0.00 AC: 0 AN: 36136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25234

East Asian (EAS) AF: 0.00 AC: 0 AN: 36608

South Asian (SAS) AF: 0.00 AC: 0 AN: 80092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49478

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5656

European-Non Finnish (NFE) AF: 0.00000646 AC: 7 AN: 1083560

Other (OTH) AF: 0.0000171 AC: 1 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.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=42/158	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs80338888; hg19: chr7-100225009; COSMIC: COSV56153710; COSMIC: COSV56153710;