3-196051968-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001128148.3(TFRC):c.2257G>A(p.Val753Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TFRC NM_001128148.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.796

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008525223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFRC	NM_001128148.3	c.2257G>A	p.Val753Ile	missense_variant	19/19	ENST00000360110.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFRC	ENST00000360110.9	c.2257G>A	p.Val753Ile	missense_variant	19/19	1	NM_001128148.3	P2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251432 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.0000791

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 753 of the TFRC protein (p.Val753Ile). This variant is present in population databases (rs141165322, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TFRC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1521743). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	10
Dann	Benign	0.51
DEOGEN2	Benign	0.0030	T;T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T;.;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.10	N;N;N
REVEL	Benign	0.064
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.068
MVP		0.15
MPC		0.13
ClinPred		0.0084	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.43

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: rs141165322; hg19: chr3-195778839; COSMIC: COSV64053826; COSMIC: COSV64053826;