3-133768114-G-C

Variant names:

• chr3-133768114-G-C
• rs8649
• NM_001063.4:c.1572G>C
• TF p.Leu524Leu

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

The NM_001063.4(TF):c.1572G>C (p.Leu524Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.245 (AC=395,066) in the gnomAD database across 1,613,778 control chromosomes, including 50,611 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.309. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5361 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45250 hom.)
• Consequence: TF NM_001063.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.621
• Publications: 1 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: Benign. The variant received -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	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).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3088 — exceeds 5%% threshold (BA1 applied)

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>C p.Leu524Leu	synonymous	Exon 13 of 17	Prot: NP_001054.2 UniProt:
	TF NM_001354703.2		c.1440G>C p.Leu480Leu	synonymous	Exon 19 of 23	Prot: NP_001341632.2
	TF NM_001354704.2		c.1191G>C p.Leu397Leu	synonymous	Exon 12 of 16	Prot: NP_001341633.2

TF NM_001063.4

MANE Select

HGVSc / HGVSpc.1572G>Cp.Leu524Leu

Exon rankExon 13 of 17

synonymous

Prot: NP_001054.2UniProt: P02787Q06AH7A0PJA6

TF NM_001354703.2

HGVSc / HGVSpc.1440G>Cp.Leu480Leu

Exon rankExon 19 of 23

synonymous

Prot: NP_001341632.2

TF NM_001354704.2

HGVSc / HGVSpc.1191G>Cp.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>C p.Leu524Leu	synonymous	Exon 13 of 17	Prot: ENSP00000385834.3 UniProt:
	TF ENST00000877249.1		c.924G>C p.Leu308Leu	synonymous	Exon 8 of 12	Prot: ENSP00000547308.1 UniProt:
	TF ENST00000877246.1		c.585G>C p.Leu195Leu	synonymous	Exon 6 of 10	Prot: ENSP00000547305.1 UniProt:

TF ENST00000402696.9

TSL:1MANE Select

HGVSc / HGVSpc.1572G>Cp.Leu524Leu

Exon rankExon 13 of 17

synonymous

Prot: ENSP00000385834.3UniProt: P02787

TF ENST00000877249.1

HGVSc / HGVSpc.924G>Cp.Leu308Leu

Exon rankExon 8 of 12

synonymous

Prot: ENSP00000547308.1UniProt: A0ACI8QAC3

TF ENST00000877246.1

HGVSc / HGVSpc.585G>Cp.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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.258	AC:39277	Hom:5358	AN:151958	Cov:32
GnomAD2 exomes	AF: 0.218	AC:54896	Hom:	AN:251394	Cov:
GnomAD4 exome	AF: 0.243	AC:355774	Hom:45250	AN:1461702	Cov:35
GnomAD4 genome	AF: 0.258	AC:39292	Hom:5361	AN:152076	Cov:32
TOPMed (Bravo)	AF: 0.253	AC:66840	Hom:9045	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.228	AC:26719	Hom:3358	AN:117208	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.260	AC:609	Hom:79	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0727	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.220	AC:66	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.276	AC:3584	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.137	AC:476	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0870	AC:632	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.211	AC:423	Hom:	AN:2008	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0913	AC:11216	Hom:501	AN:122790	Cov:
Turkish Variome	AF: 0.200	AC:1343	Hom:156	AN:6702	Cov:
UK10K	AF: 0.255	AC:1928	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0661	AC:592	Hom:24	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.261 *	2895	11106	0.254 *	4478	17608
BipEx(Bipolar disorder (including schizoaffective))	0.260	7403	28420	0.259	7475	28844
Epi25(Epilepsy)	0.241	10102	41958	0.244	16296	66884
SCHEMA(Schizophrenia)	0.249	34014	136596	0.270	61353	226904

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Atransferrinemia (1)
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	11
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.3
DANN	Benign	0.43
GPN-Star LLR	N/A	-2.4
GPN-Star score	N/A	2.4
Mutation Taster	N/A	94/6	polymorphism (auto)
PhyloP100	Benign	0.62
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.8

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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

dbSNP: rs8649;

hg19: chr3-133486958;

COSMIC: COSV53922542;

COSMIC: COSV53922542;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar