rs12769

chr3-133755484-G-Achr3-133755484-G-C

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.624G>A(p.Ser208=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,613,820 control chromosomes in the GnomAD database, including 85,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6419 hom., cov: 32)
  • Exomes 𝑓: 0.32 (79491 hom.)
• Consequence: TF NM_001063.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.60

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=-0.93).
• BP6: Variant 3-133755484-G-A is Benign according to our data. Variant chr3-133755484-G-A is described in ClinVar as [Benign]. Clinvar id is 343436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-133755484-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TF	NM_001063.4	c.624G>A	p.Ser208=	synonymous_variant	5/17	ENST00000402696.9
TF	NM_001354703.2	c.492G>A	p.Ser164=	synonymous_variant	11/23
TF	NM_001354704.2	c.243G>A	p.Ser81=	synonymous_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TF	ENST00000402696.9	c.624G>A	p.Ser208=	synonymous_variant	5/17	1	NM_001063.4	P1
TF	ENST00000482271.5	c.243G>A	p.Ser81=	synonymous_variant	4/6	4
TF	ENST00000493011.5	n.672G>A		non_coding_transcript_exon_variant	5/5	2
TF	ENST00000485977.1	c.158-1448G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41188 AN: 152044 Hom.: 6418 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.270

GnomAD3 exomes AF: 0.335 AC: 83312 AN: 248742 Hom.: 15279 AF XY: 0.336 AC XY: 45226 AN XY: 134660

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.455

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.420

Gnomad SAS exome AF: 0.411

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.323 AC: 472839 AN: 1461658 Hom.: 79491 Cov.: 47 AF XY: 0.326 AC XY: 236940 AN XY: 727142

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.442

Gnomad4 ASJ exome AF: 0.239

Gnomad4 EAS exome AF: 0.473

Gnomad4 SAS exome AF: 0.405

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.318

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.271 AC: 41202 AN: 152162 Hom.: 6419 Cov.: 32 AF XY: 0.274 AC XY: 20403 AN XY: 74388

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.405

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.271

Alfa AF: 0.291 Hom.: 8385

Bravo AF: 0.268

Asia WGS AF: 0.404 AC: 1405 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.296

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Atransferrinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.93
Cadd	Benign	0.87
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12769; hg19: chr3-133474328; COSMIC: COSV53918813; COSMIC: COSV53918813;