3-133768114-G-A

Variant names:

• chr3-133768114-G-A
• NM_001063.4:c.1572G>A
• TF p.Leu524Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP7

The NM_001063.4(TF):c.1572G>A (p.Leu524Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TF NM_001063.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.621
• Publications: 0 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, MODERATE, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, ClinGen, Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001063.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TF NM_001063.4	MANE Select	c.1572G>A p.Leu524Leu	synonymous	Exon 13 of 17	Prot: NP_001054.2 UniProt:
	TF NM_001354703.2		c.1440G>A p.Leu480Leu	synonymous	Exon 19 of 23	Prot: NP_001341632.2
	TF NM_001354704.2		c.1191G>A p.Leu397Leu	synonymous	Exon 12 of 16	Prot: NP_001341633.2

TF NM_001063.4

MANE Select

HGVSc / HGVSpc.1572G>Ap.Leu524Leu

Exon rankExon 13 of 17

synonymous

Prot: NP_001054.2UniProt: P02787Q06AH7A0PJA6

TF NM_001354703.2

HGVSc / HGVSpc.1440G>Ap.Leu480Leu

Exon rankExon 19 of 23

synonymous

Prot: NP_001341632.2

TF NM_001354704.2

HGVSc / HGVSpc.1191G>Ap.Leu397Leu

Exon rankExon 12 of 16

synonymous

Prot: NP_001341633.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TF ENST00000402696.9	TSL:1MANE Select	c.1572G>A p.Leu524Leu	synonymous	Exon 13 of 17	Prot: ENSP00000385834.3 UniProt:
	TF ENST00000877249.1		c.924G>A p.Leu308Leu	synonymous	Exon 8 of 12	Prot: ENSP00000547308.1 UniProt:
	TF ENST00000877246.1		c.585G>A p.Leu195Leu	synonymous	Exon 6 of 10	Prot: ENSP00000547305.1 UniProt:

TF ENST00000402696.9

TSL:1MANE Select

HGVSc / HGVSpc.1572G>Ap.Leu524Leu

Exon rankExon 13 of 17

synonymous

Prot: ENSP00000385834.3UniProt: P02787

TF ENST00000877249.1

HGVSc / HGVSpc.924G>Ap.Leu308Leu

Exon rankExon 8 of 12

synonymous

Prot: ENSP00000547308.1UniProt: A0ACI8QAC3

TF ENST00000877246.1

HGVSc / HGVSpc.585G>Ap.Leu195Leu

Exon rankExon 6 of 10

synonymous

Prot: ENSP00000547305.1UniProt: A0ACI8R955

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	11
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.7
DANN	Benign	0.45
GPN-Star LLR	N/A	-1.7
GPN-Star score	N/A	1.7
PhyloP100	Benign	0.62
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.8

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr3-133486958;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar