rs41295942

Variant names:

• chr7-100621008-C-T
• rs41295942
• NM_003227.4:c.2255G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-100621008-C-T
• chr7-100621008-C-A
• chr7-100621008-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003227.4(TFR2):​c.2255G>A​(p.Arg752His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 1,603,208 control chromosomes in the GnomAD database, including 683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R752C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (48 hom., cov: 32)
  • Exomes 𝑓: 0.027 (635 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.659
• Publications: 24 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005874753).
• BP6: Variant 7-100621008-C-T is Benign according to our data. Variant chr7-100621008-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0212 (3222/152314) while in subpopulation NFE AF = 0.033 (2244/68016). AF 95% confidence interval is 0.0319. There are 48 homozygotes in GnomAd4. There are 1509 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 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.2255G>A	p.Arg752His	missense	Exon 18 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.1742G>A	p.Arg581His	missense	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.2255G>A	p.Arg752His	missense	Exon 18 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.2351G>A	p.Arg784His	missense	Exon 20 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.2348G>A	p.Arg783His	missense	Exon 20 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3223 AN: 152196 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.0205 AC: 4645 AN: 226790 AF XY: 0.0209

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0304

Gnomad NFE exome AF: 0.0303

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0272 AC: 39531 AN: 1450894 Hom.: 635 Cov.: 31 AF XY: 0.0269 AC XY: 19399 AN XY: 720882

African (AFR) AF: 0.00428 AC: 142 AN: 33210

American (AMR) AF: 0.0116 AC: 498 AN: 43056

Ashkenazi Jewish (ASJ) AF: 0.0195 AC: 506 AN: 25900

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39022

South Asian (SAS) AF: 0.0100 AC: 852 AN: 84998

European-Finnish (FIN) AF: 0.0322 AC: 1686 AN: 52302

Middle Eastern (MID) AF: 0.00266 AC: 14 AN: 5260

European-Non Finnish (NFE) AF: 0.0311 AC: 34442 AN: 1107348

Other (OTH) AF: 0.0232 AC: 1390 AN: 59798

GnomAD4 genome AF: 0.0212 AC: 3222 AN: 152314 Hom.: 48 Cov.: 32 AF XY: 0.0203 AC XY: 1509 AN XY: 74480

African (AFR) AF: 0.00467 AC: 194 AN: 41578

American (AMR) AF: 0.0180 AC: 275 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4832

European-Finnish (FIN) AF: 0.0289 AC: 307 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0330 AC: 2244 AN: 68016

Other (OTH) AF: 0.0203 AC: 43 AN: 2116

Alfa AF: 0.0305 Hom.: 121

Bravo AF: 0.0188

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0281 AC: 241

ExAC AF: 0.0190 AC: 2303

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hemochromatosis type 3 (2)
-	-	1	Hereditary hemochromatosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.66
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.18
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.13
MPC		1.2
ClinPred		0.020	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.44
Mutation Taster		=86/14	polymorphism (auto)

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: rs41295942; hg19: chr7-100218631; COSMIC: COSV106381235;