rs41303495

chr7-100631032-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003227.4(TFR2):c.1127C>A(p.Ala376Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,592,294 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (20 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.54

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00885278).
• BP6: Variant 7-100631032-G-T is Benign according to our data. Variant chr7-100631032-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461196.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr7-100631032-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0037 (563/152326) while in subpopulation NFE AF= 0.00472 (321/68016). AF 95% confidence interval is 0.00429. There are 9 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFR2	NM_003227.4	c.1127C>A	p.Ala376Asp	missense_variant	9/18	ENST00000223051.8
LOC124901709	XR_007060454.1	n.434-124G>T		intron_variant, non_coding_transcript_variant
TFR2	NM_001206855.3	c.614C>A	p.Ala205Asp	missense_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.1127C>A	p.Ala376Asp	missense_variant	9/18	1	NM_003227.4	P1

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 563 AN: 152208 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00269 AC: 596 AN: 221158 Hom.: 3 AF XY: 0.00272 AC XY: 329 AN XY: 121060

Gnomad AFR exome AF: 0.000504

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00166

Gnomad FIN exome AF: 0.00156

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.00357

GnomAD4 exome AF: 0.00480 AC: 6917 AN: 1439968 Hom.: 20 Cov.: 31 AF XY: 0.00466 AC XY: 3339 AN XY: 715966

Gnomad4 AFR exome AF: 0.000713

Gnomad4 AMR exome AF: 0.00229

Gnomad4 ASJ exome AF: 0.0000808

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00149

Gnomad4 FIN exome AF: 0.00172

Gnomad4 NFE exome AF: 0.00575

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152326 Hom.: 9 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74472

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00472

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00433 Hom.: 2

Bravo AF: 0.00396

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000911 AC: 4

ESP6500EA AF: 0.00420 AC: 36

ExAC AF: 0.00255 AC: 309

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TFR2 p.A205D variant was not identified in the literature nor was it identified in Cosmic and LOVD 3.0. The variant was identified in dbSNP (ID: rs41303495) and in ClinVar (classified as likely benign by Invitae for associated condition of Hereditary Hemochromatosis). The variant was identified in control databases in 683 of 252548 chromosomes (3 homozygous) at a frequency of 0.002704 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 487 of 115588 chromosomes (freq: 0.004213), Other in 21 of 6406 chromosomes (freq: 0.003278), Latino in 76 of 30012 chromosomes (freq: 0.002532), South Asian in 46 of 27714 chromosomes (freq: 0.00166), European (Finnish) in 35 of 23298 chromosomes (freq: 0.001502), African in 17 of 22612 chromosomes (freq: 0.000752) and Ashkenazi Jewish in 1 of 8620 chromosomes (freq: 0.000116), but was not observed in the East Asian population. The p.Ala205 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hemochromatosis type 3 Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 09, 2020	- -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary hemochromatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.71	T;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0089	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	0.67	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.92	P;P
Vest4		0.50
MVP		0.74
MPC		0.91
ClinPred		0.072	T
GERP RS		3.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.37
gMVP		0.84

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: rs41303495; hg19: chr7-100228655;