rs863225436

Variant names:

• chr3-196075339-A-G
• rs863225436
• NM_001128148.3:c.58T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001128148.3(TFRC):​c.58T>C​(p.Tyr20His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TFRC NM_001128148.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 8.60

Genes affected

TFRC (HGNC:11763): (transferrin receptor) This gene encodes a cell surface receptor necessary for cellular iron uptake by the process of receptor-mediated endocytosis. This receptor is required for erythropoiesis and neurologic development. Multiple alternatively spliced variants have been identified. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a modified_residue Phosphotyrosine (size 0) in uniprot entity TFR1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 3-196075339-A-G is Pathogenic according to our data. Variant chr3-196075339-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218163.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFRC	NM_001128148.3	c.58T>C	p.Tyr20His	missense_variant	Exon 3 of 19	ENST00000360110.9	NP_001121620.1
TFRC	NM_003234.4	c.58T>C	p.Tyr20His	missense_variant	Exon 3 of 19		NP_003225.2
TFRC	NM_001313965.2	c.-5-1214T>C		intron_variant	Intron 2 of 17		NP_001300894.1
TFRC	NM_001313966.2	c.-413+1725T>C		intron_variant	Intron 2 of 16		NP_001300895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFRC	ENST00000360110.9	c.58T>C	p.Tyr20His	missense_variant	Exon 3 of 19	1	NM_001128148.3	ENSP00000353224.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

TFRC-related combined immunodeficiency Pathogenic:2 Uncertain:1

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1 Uncertain:1

Sep 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in homozygous state in multiple unrelated patients with TFRC-related immunodeficiency referred for genetic testing at GeneDx and in published literature and not observed in homozygous state in controls (PMID: 32851577, 26642240); Published functional studies suggest a damaging effect (PMID: 26642240); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34820863, 28129536, 30995720, Vorsteveld2024[casereport], 37812650, 38458303, 34518441, 33665641, 33117818, 35831434, 37192162, 37646182, 31443397, 26642240, 32851577, 38270687, 30697212) -

Apr 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 20 of the TFRC protein (p.Tyr20His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with combined immunodeficiency (PMID: 26642240, 32851577). ClinVar contains an entry for this variant (Variation ID: 218163). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Combined immunodeficiency Pathogenic:1

Jan 15, 2015

Geha Laboratory, Boston Childrens Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Patients with a combined immunodeficiency characterized by normal numbers, but impaired function, of T and B cells had a homozygous p.Tyr20His mutation in TFRC, encoding transferrin receptor 1 (TfR1). The mutation disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 surface expression. Iron citrate rescued the lymphocyte defects and transduction of wild type, but not mutant, TfR1 rescued impaired transferrin uptake in patient fibroblasts. TfrcY20H/Y20H mice recapitulated the patients’ immunologic defects. Despite the critical role of TfR1 in erythrocyte development and function, the patients had only mild anemia and only slightly TfR1 expression in their erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, can associate with TfR1 and partially rescues transferrin uptake in patient fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares the patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity. -

TFRC-related disorder Pathogenic:1

Mar 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TFRC c.58T>C variant is predicted to result in the amino acid substitution p.Tyr20His. This variant has been reported in the homozygous state in several individuals from unrelated families with combined immune deficiency (Jabara et al. 2016. PubMed ID: 26642240; Aljohani et al. 2020. PubMed ID: 32851577). Functional studies from patient-derived fibroblasts and murine models showed that this variant in the homozygous state impacted protein function (Jabara et al. 2016. PubMed ID: 26642240). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.78		Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);
MVP		0.52
MPC		0.77
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.73

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: rs863225436; hg19: chr3-195802210;