rs41295879

chr3-196064369-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001128148.3(TFRC):c.1258G>A(p.Gly420Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,613,708 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G420D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0083 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (14 hom.)
• Consequence: TFRC NM_001128148.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.35

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054885447).
• BP6: Variant 3-196064369-C-T is Benign according to our data. Variant chr3-196064369-C-T is described in ClinVar as [Benign]. Clinvar id is 708777.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00833 (1269/152252) while in subpopulation AFR AF= 0.0296 (1228/41536). AF 95% confidence interval is 0.0282. There are 21 homozygotes in gnomad4. There are 598 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFRC	NM_001128148.3	c.1258G>A	p.Gly420Ser	missense_variant	11/19	ENST00000360110.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFRC	ENST00000360110.9	c.1258G>A	p.Gly420Ser	missense_variant	11/19	1	NM_001128148.3	P2

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1269 AN: 152134 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00237 AC: 594 AN: 250990 Hom.: 9 AF XY: 0.00165 AC XY: 224 AN XY: 135706

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.000755

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000855 AC: 1250 AN: 1461456 Hom.: 14 Cov.: 30 AF XY: 0.000736 AC XY: 535 AN XY: 727068

Gnomad4 AFR exome AF: 0.0322

Gnomad4 AMR exome AF: 0.000986

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00833 AC: 1269 AN: 152252 Hom.: 21 Cov.: 32 AF XY: 0.00803 AC XY: 598 AN XY: 74454

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00175 Hom.: 6

Bravo AF: 0.00954

ESP6500AA AF: 0.0297 AC: 131

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00291 AC: 353

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	13
Dann	Benign	0.31
DEOGEN2	Benign	0.0032	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.65	T;.;T
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.54	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.82	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.019	.;B;B
Vest4		0.24
MVP		0.38
MPC		0.18
ClinPred		0.00083	T
GERP RS		-1.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.072
gMVP		0.40

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: rs41295879; hg19: chr3-195791240;