rs1799899

Variant names:

• chr3-133756968-G-A
• rs1799899
• NM_001063.4:c.829G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_001063.4(TF):​c.829G>A​(p.Gly277Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 1,614,076 control chromosomes in the GnomAD database, including 2,443 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G277D) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.045 (273 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2170 hom.)
• Consequence: TF NM_001063.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 3.28
• Publications: 59 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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-133756969-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12614.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019334853).
• BP6: Variant 3-133756968-G-A is Benign according to our data. Variant chr3-133756968-G-A is described in ClinVar as Benign. ClinVar VariationId is 12622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TF	NM_001063.4	c.829G>A	p.Gly277Ser	missense_variant	Exon 7 of 17	ENST00000402696.9	NP_001054.2
TF	NM_001354703.2	c.697G>A	p.Gly233Ser	missense_variant	Exon 13 of 23		NP_001341632.2
TF	NM_001354704.2	c.448G>A	p.Gly150Ser	missense_variant	Exon 6 of 16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TF	ENST00000402696.9	c.829G>A	p.Gly277Ser	missense_variant	Exon 7 of 17	1	NM_001063.4	ENSP00000385834.3
TF	ENST00000485977.1	n.194G>A		non_coding_transcript_exon_variant	Exon 3 of 5	3		ENSP00000418716.1
TF	ENST00000482271.5	c.*45G>A		downstream_gene_variant		4		ENSP00000419338.1

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6832 AN: 152086 Hom.: 273 Cov.: 32

Gnomad AFR AF: 0.00845

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0452

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0558

Gnomad OTH AF: 0.0407

GnomAD2 exomes AF: 0.0524 AC: 13161 AN: 251324 AF XY: 0.0541

Gnomad AFR exome AF: 0.00904

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0597

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.0585

Gnomad OTH exome AF: 0.0534

GnomAD4 exome AF: 0.0492 AC: 71868 AN: 1461872 Hom.: 2170 Cov.: 33 AF XY: 0.0494 AC XY: 35896 AN XY: 727236

African (AFR) AF: 0.00899 AC: 301 AN: 33474

American (AMR) AF: 0.0269 AC: 1201 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0621 AC: 1622 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0466 AC: 4022 AN: 86258

European-Finnish (FIN) AF: 0.143 AC: 7658 AN: 53420

Middle Eastern (MID) AF: 0.0615 AC: 355 AN: 5768

European-Non Finnish (NFE) AF: 0.0485 AC: 53878 AN: 1112000

Other (OTH) AF: 0.0468 AC: 2829 AN: 60396

GnomAD4 genome AF: 0.0449 AC: 6833 AN: 152204 Hom.: 273 Cov.: 32 AF XY: 0.0487 AC XY: 3623 AN XY: 74394

African (AFR) AF: 0.00845 AC: 351 AN: 41548

American (AMR) AF: 0.0347 AC: 531 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 214 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0456 AC: 220 AN: 4822

European-Finnish (FIN) AF: 0.153 AC: 1616 AN: 10574

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0558 AC: 3795 AN: 68006

Other (OTH) AF: 0.0403 AC: 85 AN: 2110

Alfa AF: 0.0484 Hom.: 826

Bravo AF: 0.0337

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.0476 AC: 409

ExAC AF: 0.0532 AC: 6456

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.0547

EpiControl AF: 0.0538

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 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

- -

Iron deficiency anemia Uncertain:1

Jan 01, 2006

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Atransferrinemia Benign:1

Mar 06, 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. -

TF-related disorder Benign:1

Dec 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.3
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.16
Sift	Benign	0.040	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.032
MPC		1.1
ClinPred		0.020	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.35
Mutation Taster		=87/13	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: rs1799899; hg19: chr3-133475812; COSMIC: COSV53919218; COSMIC: COSV53919218;