rs2075674

chr7-100627408-G-Achr7-100627408-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003227.4(TFR2):c.1851C>T(p.Ala617=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,568,136 control chromosomes in the GnomAD database, including 29,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2223 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26810 hom.)
• Consequence: TFR2 NM_003227.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.56

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 7-100627408-G-A is Benign according to our data. Variant chr7-100627408-G-A is described in ClinVar as [Benign]. Clinvar id is 21369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100627408-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFR2	NM_003227.4	c.1851C>T	p.Ala617=	synonymous_variant	16/18	ENST00000223051.8
LOC124901709	XR_007060454.1	n.434-3748G>A		intron_variant, non_coding_transcript_variant
TFR2	NM_001206855.3	c.1338C>T	p.Ala446=	synonymous_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.1851C>T	p.Ala617=	synonymous_variant	16/18	1	NM_003227.4	P1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24633 AN: 152140 Hom.: 2220 Cov.: 33

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.176 AC: 31394 AN: 178406 Hom.: 2983 AF XY: 0.176 AC XY: 16705 AN XY: 94862

Gnomad AFR exome AF: 0.0901

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.121

Gnomad SAS exome AF: 0.131

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.191 AC: 269930 AN: 1415878 Hom.: 26810 Cov.: 59 AF XY: 0.190 AC XY: 132885 AN XY: 700108

Gnomad4 AFR exome AF: 0.0815

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.185

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.162 AC: 24645 AN: 152258 Hom.: 2223 Cov.: 33 AF XY: 0.159 AC XY: 11862 AN XY: 74442

Gnomad4 AFR AF: 0.0890

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.154

Alfa AF: 0.189 Hom.: 3259

Bravo AF: 0.155

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 3 Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hereditary hemochromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary hemochromatosis type 4 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	1.9
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075674; hg19: chr7-100225031; COSMIC: COSV56152969; COSMIC: COSV56152969;