Genetic Variant TF:p.Leu524Leu (chr3-133768114-G-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.621

Publications

21 publications found

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 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)

TF links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001063.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

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

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

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

GnomAD3 genomes

AF:

0.258

AC:

39277

AN:

151958

Hom.:

5358

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.399

Gnomad AMR

AF:

0.188

Gnomad ASJ

AF:

0.233

Gnomad EAS

AF:

0.0679

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.316

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.253

GnomAD2 exomes

AF:

0.218

AC:

54896

AN:

251394

AF XY:

0.218

show subpopulations

Gnomad AFR exome

AF:

0.310

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.236

Gnomad EAS exome

AF:

0.0684

Gnomad FIN exome

AF:

0.314

Gnomad NFE exome

AF:

0.254

Gnomad OTH exome

AF:

0.238

GnomAD4 exome

AF:

0.243

AC:

355774

AN:

1461702

Hom.:

45250

Cov.:

AF XY:

0.240

AC XY:

174528

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.314

AC:

10504

AN:

33474

American (AMR)

AF:

0.139

AC:

6211

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

6124

AN:

26132

East Asian (EAS)

AF:

0.0798

AC:

3168

AN:

39700

South Asian (SAS)

AF:

0.148

AC:

12725

AN:

86250

European-Finnish (FIN)

AF:

0.307

AC:

16388

AN:

53414

Middle Eastern (MID)

AF:

0.235

AC:

1357

AN:

5766

European-Non Finnish (NFE)

AF:

0.256

AC:

284737

AN:

1111856

Other (OTH)

AF:

0.241

AC:

14560

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

14537

29075

43612

58150

72687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9514

19028

28542

38056

47570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.258

AC:

39292

AN:

152076

Hom.:

5361

Cov.:

AF XY:

0.255

AC XY:

18990

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.312

AC:

12927

AN:

41454

American (AMR)

AF:

0.188

AC:

2873

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

810

AN:

3470

East Asian (EAS)

AF:

0.0680

AC:

353

AN:

5190

South Asian (SAS)

AF:

0.141

AC:

682

AN:

4820

European-Finnish (FIN)

AF:

0.316

AC:

3340

AN:

10560

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.255

AC:

17333

AN:

67976

Other (OTH)

AF:

0.250

AC:

528

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1493

2986

4479

5972

7465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.229

Hom.:

3190

Bravo

AF:

0.253

Asia WGS

AF:

0.137

AC:

476

AN:

3478

EpiCase

AF:

0.250

EpiControl

AF:

0.250

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0913

AC:

11216

AN:

122790

Turkish Variome

AF:

0.200

AC:

1343

AN:

6702

Hom.:

156

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0661

AC:

592

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.260

AC:

609

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Atransferrinemia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.3

(source)

DANN

Benign

0.43

PhyloP100

0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over