7-100638970-T-C

Variant names:

• chr7-100638970-T-C
• rs4727457
• NM_003227.4:c.473+1716A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003227.4(TFR2):​c.473+1716A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.87 in 152,072 control chromosomes in the GnomAD database, including 57,856 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (57856 hom., cov: 30)
• Consequence: TFR2 NM_003227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• Publications: 6 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: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

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.473+1716A>G		intron	N/A	NP_003218.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	ENST00000223051.8	TSL:1 MANE Select	c.473+1716A>G		intron	N/A	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.512+1716A>G		intron	N/A	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.473+1716A>G		intron	N/A	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132230 AN: 151954 Hom.: 57802 Cov.: 30

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.900

Gnomad ASJ AF: 0.883

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.760

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.835

Gnomad OTH AF: 0.866

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.870 AC: 132343 AN: 152072 Hom.: 57856 Cov.: 30 AF XY: 0.868 AC XY: 64468 AN XY: 74310

African (AFR) AF: 0.948 AC: 39340 AN: 41490

American (AMR) AF: 0.900 AC: 13718 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.883 AC: 3065 AN: 3472

East Asian (EAS) AF: 0.905 AC: 4675 AN: 5168

South Asian (SAS) AF: 0.760 AC: 3664 AN: 4822

European-Finnish (FIN) AF: 0.785 AC: 8295 AN: 10564

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.835 AC: 56814 AN: 68008

Other (OTH) AF: 0.866 AC: 1827 AN: 2110

Alfa AF: 0.850 Hom.: 93216

Bravo AF: 0.885

Asia WGS AF: 0.831 AC: 2894 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.59
DANN	Benign	0.63
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4727457;

hg19: chr7-100236593;