3-133756878-C-T

Variant names:

• chr3-133756878-C-T
• rs1799852
• NM_001063.4:c.739C>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.739C>T​(p.Leu247Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,614,108 control chromosomes in the GnomAD database, including 10,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L247L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1030 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9702 hom.)
• Consequence: TF NM_001063.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.268
• Publications: 65 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, MODERATE, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, 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=-0.63).
• BP6: Variant 3-133756878-C-T is Benign according to our data. Variant chr3-133756878-C-T is described in ClinVar as Benign. ClinVar VariationId is 343439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.268 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001063.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TF	NM_001063.4	MANE Select	c.739C>T	p.Leu247Leu	synonymous	Exon 7 of 17	NP_001054.2	P02787
	TF	NM_001354703.2		c.607C>T	p.Leu203Leu	synonymous	Exon 13 of 23	NP_001341632.2
	TF	NM_001354704.2		c.358C>T	p.Leu120Leu	synonymous	Exon 6 of 16	NP_001341633.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TF	ENST00000402696.9	TSL:1 MANE Select	c.739C>T	p.Leu247Leu	synonymous	Exon 7 of 17	ENSP00000385834.3	P02787
	TF	ENST00000877249.1		c.91C>T	p.Leu31Leu	synonymous	Exon 2 of 12	ENSP00000547308.1
	TF	ENST00000482271.5	TSL:4	c.358C>T	p.Leu120Leu	synonymous	Exon 6 of 6	ENSP00000419338.1	C9JVG0

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16433 AN: 152114 Hom.: 1028 Cov.: 32

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.131 AC: 32867 AN: 251486 AF XY: 0.131

Gnomad AFR exome AF: 0.0617

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.267

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.109 AC: 159010 AN: 1461874 Hom.: 9702 Cov.: 33 AF XY: 0.110 AC XY: 80024 AN XY: 727238

African (AFR) AF: 0.0596 AC: 1997 AN: 33480

American (AMR) AF: 0.133 AC: 5954 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3193 AN: 26136

East Asian (EAS) AF: 0.225 AC: 8935 AN: 39700

South Asian (SAS) AF: 0.147 AC: 12688 AN: 86258

European-Finnish (FIN) AF: 0.166 AC: 8874 AN: 53420

Middle Eastern (MID) AF: 0.138 AC: 797 AN: 5768

European-Non Finnish (NFE) AF: 0.0983 AC: 109341 AN: 1111994

Other (OTH) AF: 0.120 AC: 7231 AN: 60394

GnomAD4 genome AF: 0.108 AC: 16433 AN: 152234 Hom.: 1030 Cov.: 32 AF XY: 0.113 AC XY: 8432 AN XY: 74414

African (AFR) AF: 0.0631 AC: 2623 AN: 41558

American (AMR) AF: 0.133 AC: 2028 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 410 AN: 3468

East Asian (EAS) AF: 0.246 AC: 1273 AN: 5174

South Asian (SAS) AF: 0.159 AC: 769 AN: 4824

European-Finnish (FIN) AF: 0.174 AC: 1845 AN: 10578

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7125 AN: 68014

Other (OTH) AF: 0.112 AC: 237 AN: 2114

Alfa AF: 0.108 Hom.: 4040

Bravo AF: 0.104

Asia WGS AF: 0.200 AC: 692 AN: 3478

EpiCase AF: 0.104

EpiControl AF: 0.107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Atransferrinemia (1)
-	-	1	TF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.5
DANN	Benign	0.83
PhyloP100		-0.27
Mutation Taster		=100/0	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: rs1799852; hg19: chr3-133475722; COSMIC: COSV53917870; COSMIC: COSV53917870;