chr3-196073940-C-T

Variant names:

• chr3-196073940-C-T
• rs3817672
• NM_001128148.3:c.424G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:4
• Conservation: PhyloP100: -1.01
• Publications: 82 publications found

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]

TFRC Gene-Disease associations (from GenCC):

• TFRC-related combined immunodeficiency

  Inheritance: AR, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128148.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFRC	NM_001128148.3	MANE Select	c.424G>A	p.Gly142Ser	missense	Exon 4 of 19	NP_001121620.1
	TFRC	NM_003234.4		c.424G>A	p.Gly142Ser	missense	Exon 4 of 19	NP_003225.2
	TFRC	NM_001313965.2		c.181G>A	p.Gly61Ser	missense	Exon 3 of 18	NP_001300894.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFRC	ENST00000360110.9	TSL:1 MANE Select	c.424G>A	p.Gly142Ser	missense	Exon 4 of 19	ENSP00000353224.4
	TFRC	ENST00000392396.7	TSL:1	c.424G>A	p.Gly142Ser	missense	Exon 4 of 19	ENSP00000376197.3
	TFRC	ENST00000420415.5	TSL:1	c.181G>A	p.Gly61Ser	missense	Exon 3 of 18	ENSP00000390133.1

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

GnomAD2 exomes AF: 0.449 AC: 112205 AN: 249668 AF XY: 0.458

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 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

African (AFR) AF: 0.215 AC: 7192 AN: 33426

American (AMR) AF: 0.359 AC: 15945 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 12281 AN: 26058

East Asian (EAS) AF: 0.183 AC: 7254 AN: 39650

South Asian (SAS) AF: 0.418 AC: 35956 AN: 86038

European-Finnish (FIN) AF: 0.515 AC: 27500 AN: 53376

Middle Eastern (MID) AF: 0.599 AC: 3439 AN: 5746

European-Non Finnish (NFE) AF: 0.560 AC: 621775 AN: 1110652

Other (OTH) AF: 0.501 AC: 30220 AN: 60298

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

African (AFR) AF: 0.228 AC: 9442 AN: 41446

American (AMR) AF: 0.410 AC: 6246 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1641 AN: 3470

East Asian (EAS) AF: 0.156 AC: 805 AN: 5166

South Asian (SAS) AF: 0.404 AC: 1944 AN: 4816

European-Finnish (FIN) AF: 0.523 AC: 5526 AN: 10572

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37487 AN: 67960

Other (OTH) AF: 0.461 AC: 974 AN: 2112

Alfa AF: 0.501 Hom.: 67720

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

TFRC-related combined immunodeficiency Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.096	T
MetaRNN	Benign	0.000050	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-1.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.022
Sift	Benign	0.58	T
Sift4G	Benign	0.84	T
Polyphen		0.0	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
Mutation Taster		=97/3	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: rs3817672; hg19: chr3-195800811; COSMIC: COSV64056155; COSMIC: COSV64056155;