rs34242818

chr7-100633241-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003227.4(TFR2):c.714C>G(p.Ile238Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00989 in 1,613,732 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I238I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.038 (331 hom., cov: 30)
  • Exomes 𝑓: 0.0069 (402 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -5.23

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001814574).
• BP6: Variant 7-100633241-G-C is Benign according to our data. Variant chr7-100633241-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 21378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100633241-G-C is described in Lovd as [Benign]. Variant chr7-100633241-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFR2	NM_003227.4	c.714C>G	p.Ile238Met	missense_variant	5/18	ENST00000223051.8
TFR2	NM_001206855.3	c.201C>G	p.Ile67Met	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.714C>G	p.Ile238Met	missense_variant	5/18	1	NM_003227.4	P1

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5811 AN: 152102 Hom.: 329 Cov.: 30

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0625

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0177 AC: 4398 AN: 248788 Hom.: 164 AF XY: 0.0161 AC XY: 2180 AN XY: 135008

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00797

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0646

Gnomad SAS exome AF: 0.0274

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000784

Gnomad OTH exome AF: 0.00987

GnomAD4 exome AF: 0.00694 AC: 10147 AN: 1461512 Hom.: 402 Cov.: 33 AF XY: 0.00717 AC XY: 5212 AN XY: 727090

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.00834

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0554

Gnomad4 SAS exome AF: 0.0242

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000463

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0382 AC: 5811 AN: 152220 Hom.: 331 Cov.: 30 AF XY: 0.0374 AC XY: 2785 AN XY: 74424

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0618

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.00741 Hom.: 32

Bravo AF: 0.0420

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.125 AC: 550

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0202 AC: 2450

Asia WGS AF: 0.0340 AC: 118 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 3 Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2022	- -
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. -

Hereditary hemochromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 18, 2020

This variant is associated with the following publications: (PMID: 30998180) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.47
Dann	Benign	0.97
DEOGEN2	Benign	0.079	T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.71	T;T;.
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	L;.;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.061
Sift	Uncertain	0.010	D;T;D
Sift4G	Uncertain	0.028	D;T;D
Polyphen		0.43	B;.;B
Vest4		0.089
MPC		0.80
ClinPred		0.033	T
GERP RS		-12
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.15
gMVP		0.46

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: rs34242818; hg19: chr7-100230864; COSMIC: COSV56154350; COSMIC: COSV56154350;