rs8649

chr3-133768114-G-Cchr3-133768114-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001063.4(TF):c.1572G>C(p.Leu524=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,613,778 control chromosomes in the GnomAD database, including 50,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5361 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45250 hom.)
• Consequence: TF NM_001063.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.621

Genes affected

TF (HGNC:11740): (transferrin) This gene encodes a glycoprotein with an approximate molecular weight of 76.5 kDa. It is thought to have been created as a result of an ancient gene duplication event that led to generation of homologous C and N-terminal domains each of which binds one ion of ferric iron. The function of this protein is to transport iron from the intestine, reticuloendothelial system, and liver parenchymal cells to all proliferating cells in the body. This protein may also have a physiologic role as granulocyte/pollen-binding protein (GPBP) involved in the removal of certain organic matter and allergens from serum. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 3-133768114-G-C is Benign according to our data. Variant chr3-133768114-G-C is described in ClinVar as [Benign]. Clinvar id is 343444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-133768114-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.621 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TF	NM_001063.4	c.1572G>C	p.Leu524=	synonymous_variant	13/17	ENST00000402696.9
TF	NM_001354703.2	c.1440G>C	p.Leu480=	synonymous_variant	19/23
TF	NM_001354704.2	c.1191G>C	p.Leu397=	synonymous_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TF	ENST00000402696.9	c.1572G>C	p.Leu524=	synonymous_variant	13/17	1	NM_001063.4	P1
TF	ENST00000462495.1	n.83G>C		non_coding_transcript_exon_variant	1/2	2
TF	ENST00000461695.1	c.243G>C	p.Leu81=	synonymous_variant, NMD_transcript_variant	2/7	3

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39277 AN: 151958 Hom.: 5358 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.0679

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.253

GnomAD3 exomes AF: 0.218 AC: 54896 AN: 251394 Hom.: 6749 AF XY: 0.218 AC XY: 29601 AN XY: 135864

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.0684

Gnomad SAS exome AF: 0.149

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.243 AC: 355774 AN: 1461702 Hom.: 45250 Cov.: 35 AF XY: 0.240 AC XY: 174528 AN XY: 727162

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.0798

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.307

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.241

GnomAD4 genome AF: 0.258 AC: 39292 AN: 152076 Hom.: 5361 Cov.: 32 AF XY: 0.255 AC XY: 18990 AN XY: 74350

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.233

Gnomad4 EAS AF: 0.0680

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.316

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.250

Alfa AF: 0.229 Hom.: 3190

Bravo AF: 0.253

Asia WGS AF: 0.137 AC: 476 AN: 3478

EpiCase AF: 0.250

EpiControl AF: 0.250

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atransferrinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.3
Dann	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs8649; hg19: chr3-133486958; COSMIC: COSV53922542; COSMIC: COSV53922542;