rs41295912

chr7-100627570-G-Achr7-100627570-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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:6
• Conservation: PhyloP100: 0.228

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]

LOC124901709 (HGNC:):

ACMG classification

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 GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFR2	NM_003227.4	c.1767+7C>T		splice_region_variant, intron_variant		ENST00000223051.8
LOC124901709	XR_007060454.1	n.434-3586G>A		intron_variant, non_coding_transcript_variant
TFR2	NM_001206855.3	c.1254+7C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.1767+7C>T		splice_region_variant, intron_variant		1	NM_003227.4	P1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 904 AN: 152194 Hom.: 6 Cov.: 33

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.: 17 AF XY: 0.00735 AC XY: 998 AN XY: 135712

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.: 66 Cov.: 40 AF XY: 0.00767 AC XY: 5575 AN XY: 727200

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.: 6 Cov.: 33 AF XY: 0.00553 AC XY: 412 AN XY: 74470

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.: 6

Bravo AF: 0.00497

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00700

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:2

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+	-	- -

Hereditary hemochromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

TFR2-related disorder Benign:1

Benign, criteria provided, single submitter

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	13
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

Other links and lift over

dbSNP: rs41295912; hg19: chr7-100225193;