7-100620715-C-T

Variant names:

• chr7-100620715-C-T
• rs578087339
• NM_003227.4:c.*142G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003227.4(TFR2):​c.*142G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,187,232 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: TFR2 NM_003227.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.803
• Publications: 0 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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00158 (240/152150) while in subpopulation NFE AF = 0.00256 (174/67996). AF 95% confidence interval is 0.00225. There are 1 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 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.*142G>A		3_prime_UTR	Exon 18 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.*142G>A		3_prime_UTR	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.*142G>A		3_prime_UTR	Exon 18 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.*142G>A		3_prime_UTR	Exon 20 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.*142G>A		3_prime_UTR	Exon 20 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152030 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.00336

GnomAD4 exome AF: 0.00212 AC: 2190 AN: 1035082 Hom.: 4 Cov.: 13 AF XY: 0.00213 AC XY: 1096 AN XY: 515028

African (AFR) AF: 0.000452 AC: 11 AN: 24352

American (AMR) AF: 0.000922 AC: 29 AN: 31464

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 48 AN: 19284

East Asian (EAS) AF: 0.0000586 AC: 2 AN: 34124

South Asian (SAS) AF: 0.00169 AC: 108 AN: 63910

European-Finnish (FIN) AF: 0.000127 AC: 6 AN: 47260

Middle Eastern (MID) AF: 0.00388 AC: 15 AN: 3870

European-Non Finnish (NFE) AF: 0.00244 AC: 1867 AN: 765360

Other (OTH) AF: 0.00229 AC: 104 AN: 45458

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152150 Hom.: 1 Cov.: 31 AF XY: 0.00140 AC XY: 104 AN XY: 74392

African (AFR) AF: 0.000506 AC: 21 AN: 41516

American (AMR) AF: 0.00118 AC: 18 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4814

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 67996

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00151

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.41
DANN	Benign	0.33
PhyloP100		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs578087339; hg19: chr7-100218338;