rs12769

Variant names:

• chr3-133755484-G-A
• rs12769
• NM_001063.4:c.624G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-133755484-G-A
• chr3-133755484-G-C
• chr3-133755484-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001063.4(TF):​c.624G>A​(p.Ser208Ser) 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:5
• Conservation: PhyloP100: -3.60
• Publications: 23 publications found

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]

TF Gene-Disease associations (from GenCC):

• atransferrinemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 343436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
TF	NM_001063.4	c.624G>A	p.Ser208Ser	synonymous_variant	Exon 5 of 17	ENST00000402696.9	NP_001054.2
TF	NM_001354703.2	c.492G>A	p.Ser164Ser	synonymous_variant	Exon 11 of 23		NP_001341632.2
TF	NM_001354704.2	c.243G>A	p.Ser81Ser	synonymous_variant	Exon 4 of 16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TF	ENST00000402696.9	c.624G>A	p.Ser208Ser	synonymous_variant	Exon 5 of 17	1	NM_001063.4	ENSP00000385834.3

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

GnomAD2 exomes AF: 0.335 AC: 83312 AN: 248742 AF XY: 0.336

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 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

African (AFR) AF: 0.116 AC: 3886 AN: 33480

American (AMR) AF: 0.442 AC: 19749 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6244 AN: 26136

East Asian (EAS) AF: 0.473 AC: 18793 AN: 39694

South Asian (SAS) AF: 0.405 AC: 34967 AN: 86248

European-Finnish (FIN) AF: 0.304 AC: 16226 AN: 53330

Middle Eastern (MID) AF: 0.192 AC: 1108 AN: 5768

European-Non Finnish (NFE) AF: 0.318 AC: 353484 AN: 1111898

Other (OTH) AF: 0.304 AC: 18382 AN: 60396

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

African (AFR) AF: 0.131 AC: 5432 AN: 41528

American (AMR) AF: 0.344 AC: 5258 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3470

East Asian (EAS) AF: 0.440 AC: 2274 AN: 5172

South Asian (SAS) AF: 0.405 AC: 1954 AN: 4820

European-Finnish (FIN) AF: 0.299 AC: 3160 AN: 10576

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21390 AN: 67980

Other (OTH) AF: 0.271 AC: 573 AN: 2116

Alfa AF: 0.282 Hom.: 11237

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Atransferrinemia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.87
DANN	Benign	0.83
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12769; hg19: chr3-133474328; COSMIC: COSV53918813; COSMIC: COSV53918813;