chr3-133768114-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: 21 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

Our verdict: Benign. The variant received -17 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BP6: ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
• BP7: Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
• BA1: 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	NP_001054.2	P02787
	TF	NM_001354703.2		c.1440G>C	p.Leu480Leu	synonymous	Exon 19 of 23	NP_001341632.2
	TF	NM_001354704.2		c.1191G>C	p.Leu397Leu	synonymous	Exon 12 of 16	NP_001341633.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TF	ENST00000402696.9	TSL:1 MANE Select	c.1572G>C	p.Leu524Leu	synonymous	Exon 13 of 17	ENSP00000385834.3	P02787
	TF	ENST00000877249.1		c.924G>C	p.Leu308Leu	synonymous	Exon 8 of 12	ENSP00000547308.1	A0ACI8QAC3
	TF	ENST00000877246.1		c.585G>C	p.Leu195Leu	synonymous	Exon 6 of 10	ENSP00000547305.1	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	0.258	39277	5358	151958	32
GnomAD2 exomes	0.218	54896		251394
GnomAD4 exome	0.243	355774	45250	1461702	35
GnomAD4 genome	0.258	39292	5361	152076	32
TOPMed (Bravo)	0.253	66840	9045	264690
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.228	26719	3358	117208
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.260	609	79	2342
ChinaMAP Phase 1	0.0727
Denmark Genome	0.220	66		300
ESP6500 (Exome Variant Server)	0.276	3584		13006
GenomeAsia100K	0.137	476		3478
Korea4K (4,157 Koreans)	0.0870	632		7234
Qatari Genome	0.211	423		2008
ToMMo 61KJPN (+60KJPN MNV)	0.0913	11216	501	122790
Turkish Variome	0.200	1343	156	6702
UK10K	0.255	1928		7562
WBBC (Westlake BioBank for Chinese) pilot	0.0661	592	24	8960

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 prediction	Prediction	Score
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	polymorphism (auto)	94/6
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 prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

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.

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