chr7-100627570-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003227.4(TFR2):c.1767+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00729 in 1,614,130 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0074 ( 66 hom. )

Consequence

TFR2
NM_003227.4 splice_region, intron

Scores

Splicing: ADA: 0.01185

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.228

Variant links:

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 links:

LOC124901709 (HGNC:):

LOC124901709 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 7-100627570-G-A is Benign according to our data. Variant chr7-100627570-G-A is described in ClinVar as [Benign]. Clinvar id is 415943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100627570-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00593 (903/152312) while in subpopulation SAS AF= 0.0106 (51/4830). AF 95% confidence interval is 0.00825. There are 6 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4 link	c.1767+7C>T	splice_region_variant, intron_variant	Intron 15 of 17	ENST00000223051.8	NP_003218.2	Q9UP52-1
TFR2	NM_001206855.3 link	c.1254+7C>T	splice_region_variant, intron_variant	Intron 12 of 14		NP_001193784.1	Q9UP52-2
LOC124901709	XR_007060454.1 link	n.434-3586G>A	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.1767+7C>T		splice_region_variant, intron_variant	Intron 15 of 17	1	NM_003227.4	ENSP00000223051.3		Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.00594

AC:

904

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.00649

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00773

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00703

AC:

1766

AN:

251060

Hom.:

AF XY:

0.00735

AC XY:

998

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.0303

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0123

Gnomad FIN exome

AF:

0.00616

Gnomad NFE exome

AF:

0.00693

Gnomad OTH exome

AF:

0.00849

GnomAD4 exome

AF:

0.00743

AC:

10861

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00767

AC XY:

5575

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.00291

Gnomad4 ASJ exome

AF:

0.0304

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0130

Gnomad4 FIN exome

AF:

0.00622

Gnomad4 NFE exome

AF:

0.00702

Gnomad4 OTH exome

AF:

0.00874

GnomAD4 genome

AF:

0.00593

AC:

903

AN:

152312

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

412

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.0325

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.00649

Gnomad4 NFE

AF:

0.00773

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00821

Hom.:

Bravo

AF:

0.00497

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00700

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TFR2: BP4, BS1, BS2 -

Hemochromatosis type 3

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Hereditary hemochromatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 02, 2025

- -

TFR2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.15

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over