chr3-133757854-A-G

Position:

chr3-133757854-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001063.4(TF):c.956A>G(p.His319Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,206 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 16 hom. )

Consequence

TF
NM_001063.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:2

Conservation

PhyloP100: 0.700

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056921214).

BP6

Variant 3-133757854-A-G is Benign according to our data. Variant chr3-133757854-A-G is described in ClinVar as [Benign]. Clinvar id is 12615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-133757854-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00246 (375/152320) while in subpopulation EAS AF= 0.0191 (99/5186). AF 95% confidence interval is 0.016. There are 1 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TF	NM_001063.4 linkuse as main transcript	c.956A>G	p.His319Arg	missense_variant	8/17	ENST00000402696.9	NP_001054.2	P02787Q06AH7A0PJA6
TF	NM_001354703.2 linkuse as main transcript	c.824A>G	p.His275Arg	missense_variant	14/23		NP_001341632.2
TF	NM_001354704.2 linkuse as main transcript	c.575A>G	p.His192Arg	missense_variant	7/16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TF	ENST00000402696.9 linkuse as main transcript	c.956A>G	p.His319Arg	missense_variant	8/17	1	NM_001063.4	ENSP00000385834.3	P02787
TF	ENST00000485977.1 linkuse as main transcript	n.*12A>G		non_coding_transcript_exon_variant	4/5	3		ENSP00000418716.1	F8WC57
TF	ENST00000485977.1 linkuse as main transcript	n.*12A>G		3_prime_UTR_variant	4/5	3		ENSP00000418716.1	F8WC57

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0192

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00904

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00329

AC:

827

AN:

251482

Hom.:

AF XY:

0.00315

AC XY:

428

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0192

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.0104

Gnomad NFE exome

AF:

0.000510

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00109

AC:

1599

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

819

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00463

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0127

Gnomad4 SAS exome

AF:

0.000858

Gnomad4 FIN exome

AF:

0.00994

Gnomad4 NFE exome

AF:

0.000151

Gnomad4 OTH exome

AF:

0.00185

GnomAD4 genome

AF:

0.00246

AC:

375

AN:

152320

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00856

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0191

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00904

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.000880

Hom.:

Bravo

AF:

0.00158

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00274

AC:

333

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Transferrin variant D(Chi)

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1984

- -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.8

DANN

Benign

0.68

DEOGEN2

Benign

0.21

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.037

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.56

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.5

REVEL

Benign

0.037

Sift

Benign

0.37

Sift4G

Benign

0.39

Polyphen

0.070

Vest4

0.097

MVP

0.29

MPC

0.40

ClinPred

0.017

GERP RS

-5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.17

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over