rs121918678

Variant names:

• chr3-133777112-A-G
• rs121918678
• NM_001063.4:c.1936A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001063.4(TF):​c.1936A>G​(p.Lys646Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. K646K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TF NM_001063.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.69
• Publications: 3 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-133777112-A-G is Pathogenic according to our data. Variant chr3-133777112-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12618.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TF	NM_001063.4	c.1936A>G	p.Lys646Glu	missense_variant	Exon 16 of 17	ENST00000402696.9	NP_001054.2
TF	NM_001354703.2	c.1804A>G	p.Lys602Glu	missense_variant	Exon 22 of 23		NP_001341632.2
TF	NM_001354704.2	c.1555A>G	p.Lys519Glu	missense_variant	Exon 15 of 16		NP_001341633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TF	ENST00000402696.9	c.1936A>G	p.Lys646Glu	missense_variant	Exon 16 of 17	1	NM_001063.4	ENSP00000385834.3
TF	ENST00000467842.1	n.2930A>G		non_coding_transcript_exon_variant	Exon 2 of 2	1
TF	ENST00000461695.1	n.*236A>G		non_coding_transcript_exon_variant	Exon 6 of 7	3		ENSP00000419714.1
TF	ENST00000461695.1	n.*236A>G		3_prime_UTR_variant	Exon 6 of 7	3		ENSP00000419714.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Transferrin variant Bv Pathogenic:1

May 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.7
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.14
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.039	D
Polyphen		0.83	P
Vest4		0.51
MutPred		0.28		Loss of ubiquitination at K646 (P = 0.027);
MVP		0.79
MPC		0.69
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.50
Mutation Taster		=28/72	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918678; hg19: chr3-133495956;