rs141140309

Variant names:

• chr7-100621091-T-C
• rs141140309
• NM_003227.4:c.2172A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003227.4(TFR2):​c.2172A>G​(p.Pro724Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,539,742 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (3 hom.)
• Consequence: TFR2 NM_003227.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -3.19
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 7-100621091-T-C is Benign according to our data. Variant chr7-100621091-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358286.
• BP7: Synonymous conserved (PhyloP=-3.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00114 (174/152216) while in subpopulation NFE AF = 0.00212 (144/68010). AF 95% confidence interval is 0.00184. There are 0 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.2172A>G	p.Pro724Pro	synonymous	Exon 18 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.1659A>G	p.Pro553Pro	synonymous	Exon 15 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.2172A>G	p.Pro724Pro	synonymous	Exon 18 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.2268A>G	p.Pro756Pro	synonymous	Exon 20 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.2265A>G	p.Pro755Pro	synonymous	Exon 20 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00114 AC: 175 AN: 153764 AF XY: 0.00127

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.000244

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00124

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.000687

GnomAD4 exome AF: 0.00215 AC: 2990 AN: 1387526 Hom.: 3 Cov.: 31 AF XY: 0.00212 AC XY: 1442 AN XY: 681748

African (AFR) AF: 0.000476 AC: 15 AN: 31494

American (AMR) AF: 0.000282 AC: 10 AN: 35516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24906

East Asian (EAS) AF: 0.00 AC: 0 AN: 35468

South Asian (SAS) AF: 0.0000380 AC: 3 AN: 78898

European-Finnish (FIN) AF: 0.00128 AC: 63 AN: 49216

Middle Eastern (MID) AF: 0.00259 AC: 12 AN: 4632

European-Non Finnish (NFE) AF: 0.00262 AC: 2808 AN: 1070016

Other (OTH) AF: 0.00138 AC: 79 AN: 57380

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74422

African (AFR) AF: 0.000482 AC: 20 AN: 41534

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00192 Hom.: 1

Bravo AF: 0.00115

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hemochromatosis type 3 (2)
-	-	1	Hereditary hemochromatosis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.41
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141140309; hg19: chr7-100218714;