NM_001063.4:c.-2A>G

Variant names:

• chr3-133746439-A-G
• rs1130459
• NM_001063.4:c.-2A>G

Variant summary

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

The NM_001063.4(TF):​c.-2A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 1,597,522 control chromosomes in the GnomAD database, including 253,921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26486 hom., cov: 33)
  • Exomes 𝑓: 0.56 (227435 hom.)
• Consequence: TF NM_001063.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.243
• Publications: 26 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=-0.69).
• BP6: Variant 3-133746439-A-G is Benign according to our data. Variant chr3-133746439-A-G is described in ClinVar as Benign. ClinVar VariationId is 343422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TF	NM_001063.4	c.-2A>G		5_prime_UTR_variant	Exon 1 of 17	ENST00000402696.9	NP_001054.2
TF	NM_001354704.2	c.-210A>G		5_prime_UTR_variant	Exon 1 of 16		NP_001341633.2
TF	NM_001354703.2	c.-89-1973A>G		intron_variant	Intron 7 of 22		NP_001341632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TF	ENST00000402696.9	c.-2A>G		5_prime_UTR_variant	Exon 1 of 17	1	NM_001063.4	ENSP00000385834.3

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88821 AN: 151988 Hom.: 26442 Cov.: 33

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.551

GnomAD2 exomes AF: 0.600 AC: 129943 AN: 216564 AF XY: 0.595

Gnomad AFR exome AF: 0.647

Gnomad AMR exome AF: 0.733

Gnomad ASJ exome AF: 0.519

Gnomad EAS exome AF: 0.769

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.540

GnomAD4 exome AF: 0.556 AC: 803527 AN: 1445416 Hom.: 227435 Cov.: 53 AF XY: 0.559 AC XY: 401412 AN XY: 718488

African (AFR) AF: 0.646 AC: 21438 AN: 33208

American (AMR) AF: 0.723 AC: 31472 AN: 43552

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 13572 AN: 25942

East Asian (EAS) AF: 0.766 AC: 29858 AN: 38988

South Asian (SAS) AF: 0.688 AC: 57933 AN: 84250

European-Finnish (FIN) AF: 0.503 AC: 23654 AN: 47066

Middle Eastern (MID) AF: 0.425 AC: 2320 AN: 5456

European-Non Finnish (NFE) AF: 0.533 AC: 589888 AN: 1107122

Other (OTH) AF: 0.558 AC: 33392 AN: 59832

GnomAD4 genome AF: 0.585 AC: 88921 AN: 152106 Hom.: 26486 Cov.: 33 AF XY: 0.586 AC XY: 43560 AN XY: 74350

African (AFR) AF: 0.651 AC: 27023 AN: 41510

American (AMR) AF: 0.637 AC: 9752 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1774 AN: 3472

East Asian (EAS) AF: 0.757 AC: 3888 AN: 5136

South Asian (SAS) AF: 0.702 AC: 3390 AN: 4826

European-Finnish (FIN) AF: 0.500 AC: 5286 AN: 10580

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.532 AC: 36166 AN: 67960

Other (OTH) AF: 0.557 AC: 1178 AN: 2116

Alfa AF: 0.543 Hom.: 29886

Bravo AF: 0.598

Asia WGS AF: 0.756 AC: 2627 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

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	-0.69
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		0.24
PromoterAI		-0.26	Neutral
Mutation Taster		=299/1	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: rs1130459; hg19: chr3-133465283; COSMIC: COSV53922246; COSMIC: COSV53922246;