3-133746439-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:3
• Conservation: PhyloP100: 0.243

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 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 id is 343422.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-133746439-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
TF	NM_001063.4	c.-2A>G		5_prime_UTR_variant	1/17	ENST00000402696.9
TF	NM_001354704.2	c.-210A>G		5_prime_UTR_variant	1/16
TF	NM_001354703.2	c.-89-1973A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TF	ENST00000402696.9	c.-2A>G		5_prime_UTR_variant	1/17	1	NM_001063.4	P1
	ENST00000460564.5	n.382-7156A>G		intron_variant, non_coding_transcript_variant		4

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

GnomAD3 exomes AF: 0.600 AC: 129943 AN: 216564 Hom.: 40335 AF XY: 0.595 AC XY: 70886 AN XY: 119200

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 SAS exome AF: 0.690

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

Gnomad4 AFR exome AF: 0.646

Gnomad4 AMR exome AF: 0.723

Gnomad4 ASJ exome AF: 0.523

Gnomad4 EAS exome AF: 0.766

Gnomad4 SAS exome AF: 0.688

Gnomad4 FIN exome AF: 0.503

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.558

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

Gnomad4 AFR AF: 0.651

Gnomad4 AMR AF: 0.637

Gnomad4 ASJ AF: 0.511

Gnomad4 EAS AF: 0.757

Gnomad4 SAS AF: 0.702

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.532

Gnomad4 OTH AF: 0.557

Alfa AF: 0.542 Hom.: 25615

Bravo AF: 0.598

Asia WGS AF: 0.756 AC: 2627 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Atransferrinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs1130459; hg19: chr3-133465283; COSMIC: COSV53922246; COSMIC: COSV53922246;