dbSNP rs121918679: TF:p.Ala477Thr (chr3-133766376-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001063.4(TF):c.1429G>A(p.Ala477Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A477P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TF
NM_001063.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.48

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 Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-133766376-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12620.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TF	NM_001063.4 link	c.1429G>A	p.Ala477Thr	missense_variant	Exon 12 of 17	ENST00000402696.9	NP_001054.2	P02787Q06AH7A0PJA6
TF	NM_001354703.2 link	c.1297G>A	p.Ala433Thr	missense_variant	Exon 18 of 23		NP_001341632.2
TF	NM_001354704.2 link	c.1048G>A	p.Ala350Thr	missense_variant	Exon 11 of 16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TF	ENST00000402696.9 link	c.1429G>A	p.Ala477Thr	missense_variant	Exon 12 of 17	1	NM_001063.4	ENSP00000385834.3		P02787
TF	ENST00000461695.1 link	n.97G>A		non_coding_transcript_exon_variant	Exon 1 of 7	3		ENSP00000419714.1		H7C5E8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251420

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000731

Hom.:

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.080

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.64

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.89

MutPred

0.91

Loss of methylation at R475 (P = 0.1372);

MVP

0.88

MPC

1.1

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.88

gMVP

0.80

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over