rs3817672

Positions:

• chr3-196073940-C-T

Variant summary

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

The NM_001128148.3(TFRC):​c.424G>A​(p.Gly142Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,611,674 control chromosomes in the GnomAD database, including 220,542 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.42 (15436 hom., cov: 31)
  • Exomes 𝑓: 0.52 (205106 hom.)
• Consequence: TFRC NM_001128148.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.01

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.010613E-5).
• BP6: Variant 3-196073940-C-T is Benign according to our data. Variant chr3-196073940-C-T is described in ClinVar as [Benign]. Clinvar id is 1164902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFRC	NM_001128148.3	c.424G>A	p.Gly142Ser	missense_variant	4/19	ENST00000360110.9
TFRC	NM_003234.4	c.424G>A	p.Gly142Ser	missense_variant	4/19
TFRC	NM_001313965.2	c.181G>A	p.Gly61Ser	missense_variant	3/18
TFRC	NM_001313966.2	c.-412-1788G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFRC	ENST00000360110.9	c.424G>A	p.Gly142Ser	missense_variant	4/19	1	NM_001128148.3	P2

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64547 AN: 151876 Hom.: 15433 Cov.: 31

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.466

GnomAD3 exomes AF: 0.449 AC: 112205 AN: 249668 Hom.: 27642 AF XY: 0.458 AC XY: 61748 AN XY: 134948

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.351

Gnomad ASJ exome AF: 0.472

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.414

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.490

GnomAD4 exome AF: 0.522 AC: 761562 AN: 1459680 Hom.: 205106 Cov.: 43 AF XY: 0.520 AC XY: 377245 AN XY: 726008

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.359

Gnomad4 ASJ exome AF: 0.471

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.418

Gnomad4 FIN exome AF: 0.515

Gnomad4 NFE exome AF: 0.560

Gnomad4 OTH exome AF: 0.501

GnomAD4 genome AF: 0.425 AC: 64554 AN: 151994 Hom.: 15436 Cov.: 31 AF XY: 0.421 AC XY: 31284 AN XY: 74298

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.473

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.461

Alfa AF: 0.517 Hom.: 51694

Bravo AF: 0.405

TwinsUK AF: 0.563 AC: 2086

ALSPAC AF: 0.560 AC: 2159

ESP6500AA AF: 0.228 AC: 1004

ESP6500EA AF: 0.546 AC: 4692

ExAC AF: 0.445 AC: 54070

Asia WGS AF: 0.309 AC: 1075 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TFRC-related combined immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.0
DANN	Benign	0.82
DEOGEN2	Benign	0.0016	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.096	T;.;T
MetaRNN	Benign	0.000050	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.020
MPC		0.16
ClinPred		0.0037	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.34

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: rs3817672; hg19: chr3-195800811; COSMIC: COSV64056155; COSMIC: COSV64056155;