chr3-133768114-G-C

Variant names:

• chr3-133768114-G-C
• rs8649
• NM_001063.4:c.1572G>C

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.1572G>C​(p.Leu524Leu) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L524L) has been classified as Likely 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:3
• Conservation: PhyloP100: 0.621
• Publications: 21 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=-0.65).
• BP6: Variant 3-133768114-G-C is Benign according to our data. Variant chr3-133768114-G-C is described in ClinVar as Benign. ClinVar VariationId is 343444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1572G>C	p.Leu524Leu	synonymous	Exon 13 of 17	NP_001054.2	P02787
	TF	NM_001354703.2		c.1440G>C	p.Leu480Leu	synonymous	Exon 19 of 23	NP_001341632.2
	TF	NM_001354704.2		c.1191G>C	p.Leu397Leu	synonymous	Exon 12 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.1572G>C	p.Leu524Leu	synonymous	Exon 13 of 17	ENSP00000385834.3	P02787
	TF	ENST00000877249.1		c.924G>C	p.Leu308Leu	synonymous	Exon 8 of 12	ENSP00000547308.1
	TF	ENST00000877246.1		c.585G>C	p.Leu195Leu	synonymous	Exon 6 of 10	ENSP00000547305.1

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

GnomAD2 exomes AF: 0.218 AC: 54896 AN: 251394 AF XY: 0.218

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 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

African (AFR) AF: 0.314 AC: 10504 AN: 33474

American (AMR) AF: 0.139 AC: 6211 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6124 AN: 26132

East Asian (EAS) AF: 0.0798 AC: 3168 AN: 39700

South Asian (SAS) AF: 0.148 AC: 12725 AN: 86250

European-Finnish (FIN) AF: 0.307 AC: 16388 AN: 53414

Middle Eastern (MID) AF: 0.235 AC: 1357 AN: 5766

European-Non Finnish (NFE) AF: 0.256 AC: 284737 AN: 1111856

Other (OTH) AF: 0.241 AC: 14560 AN: 60394

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

African (AFR) AF: 0.312 AC: 12927 AN: 41454

American (AMR) AF: 0.188 AC: 2873 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 810 AN: 3470

East Asian (EAS) AF: 0.0680 AC: 353 AN: 5190

South Asian (SAS) AF: 0.141 AC: 682 AN: 4820

European-Finnish (FIN) AF: 0.316 AC: 3340 AN: 10560

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17333 AN: 67976

Other (OTH) AF: 0.250 AC: 528 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.3
DANN	Benign	0.43
PhyloP100		0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=94/6	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: rs8649; hg19: chr3-133486958; COSMIC: COSV53922542; COSMIC: COSV53922542;