ENST00000474287.5:n.30G>T

Variant names:

• chr3-133746357-G-T
• rs8177186
• ENST00000474287.5:n.30G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000474287.5(TF):​n.30G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,500,568 control chromosomes in the GnomAD database, including 4,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (697 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3889 hom.)
• Consequence: TF ENST00000474287.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• Publications: 12 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

ENSG00000291042 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-133746357-G-T is Benign according to our data. Variant chr3-133746357-G-T is described in ClinVar as Benign. ClinVar VariationId is 343420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TF	NM_001354703.2	c.-89-2055G>T		intron_variant	Intron 7 of 22		NP_001341632.2
TF	NM_001063.4	c.-84G>T		upstream_gene_variant		ENST00000402696.9	NP_001054.2
TF	NM_001354704.2	c.-292G>T		upstream_gene_variant			NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TF	ENST00000402696.9	c.-84G>T		upstream_gene_variant		1	NM_001063.4	ENSP00000385834.3

Frequencies

GnomAD3 genomes AF: 0.0821 AC: 12486 AN: 152166 Hom.: 692 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0509

Gnomad OTH AF: 0.0870

GnomAD4 exome AF: 0.0623 AC: 84002 AN: 1348282 Hom.: 3889 Cov.: 23 AF XY: 0.0637 AC XY: 42511 AN XY: 667740

African (AFR) AF: 0.114 AC: 3486 AN: 30646

American (AMR) AF: 0.109 AC: 3900 AN: 35794

Ashkenazi Jewish (ASJ) AF: 0.0650 AC: 1619 AN: 24912

East Asian (EAS) AF: 0.239 AC: 8480 AN: 35478

South Asian (SAS) AF: 0.110 AC: 8573 AN: 78254

European-Finnish (FIN) AF: 0.0205 AC: 844 AN: 41098

Middle Eastern (MID) AF: 0.0850 AC: 471 AN: 5538

European-Non Finnish (NFE) AF: 0.0502 AC: 52159 AN: 1039964

Other (OTH) AF: 0.0790 AC: 4470 AN: 56598

GnomAD4 genome AF: 0.0821 AC: 12506 AN: 152286 Hom.: 697 Cov.: 33 AF XY: 0.0828 AC XY: 6165 AN XY: 74460

African (AFR) AF: 0.115 AC: 4777 AN: 41562

American (AMR) AF: 0.106 AC: 1627 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3468

East Asian (EAS) AF: 0.265 AC: 1368 AN: 5158

South Asian (SAS) AF: 0.128 AC: 618 AN: 4822

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10626

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0509 AC: 3462 AN: 68020

Other (OTH) AF: 0.0894 AC: 189 AN: 2114

Alfa AF: 0.0300 Hom.: 30

Bravo AF: 0.0908

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.54
PhyloP100		0.0
PromoterAI		-0.14	Neutral
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs8177186; hg19: chr3-133465201; COSMIC: COSV53923722; COSMIC: COSV53923722;