Genetic Variant TFRC:c.-249C>T (chr3-196082268-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001128148.3(TFRC):c.-249C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 205,524 control chromosomes in the GnomAD database, including 11,560 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 8141 hom., cov: 34)

Exomes 𝑓: 0.34 ( 3419 hom. )

Consequence

TFRC
NM_001128148.3 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.993

Publications

34 publications found

Variant links:

Genes affected

TFRC (HGNC:11763): (transferrin receptor) This gene encodes a cell surface receptor necessary for cellular iron uptake by the process of receptor-mediated endocytosis. This receptor is required for erythropoiesis and neurologic development. Multiple alternatively spliced variants have been identified. [provided by RefSeq, Sep 2015]

TFRC Gene-Disease associations (from GenCC):

TFRC-related combined immunodeficiency
Inheritance: AR, Unknown Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

TFRC links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128148.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TFRC	NM_001128148.3	MANE Select	c.-249C>T	upstream_gene	N/A	NP_001121620.1	P02786
TFRC	NM_003234.4		c.-461C>T	upstream_gene	N/A	NP_003225.2	P02786
TFRC	NM_001313965.2		c.-290C>T	upstream_gene	N/A	NP_001300894.1	G3V0E5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TFRC	ENST00000360110.9	TSL:1 MANE Select	c.-249C>T	upstream_gene	N/A	ENSP00000353224.4	P02786
TFRC	ENST00000392396.7	TSL:1	c.-461C>T	upstream_gene	N/A	ENSP00000376197.3	P02786
TFRC	ENST00000420415.5	TSL:1	c.-290C>T	upstream_gene	N/A	ENSP00000390133.1	G3V0E5

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47051

AN:

151142

Hom.:

8133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.179

Gnomad AMI

AF:

0.279

Gnomad AMR

AF:

0.315

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.0779

Gnomad SAS

AF:

0.256

Gnomad FIN

AF:

0.385

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.334

GnomAD4 exome

AF:

0.335

AC:

18199

AN:

54264

Hom.:

3419

AF XY:

0.339

AC XY:

9579

AN XY:

28248

show subpopulations

African (AFR)

AF:

0.147

AC:

200

AN:

1356

American (AMR)

AF:

0.290

AC:

413

AN:

1422

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

526

AN:

1662

East Asian (EAS)

AF:

0.0815

AC:

535

AN:

6564

South Asian (SAS)

AF:

0.273

AC:

117

AN:

428

European-Finnish (FIN)

AF:

0.365

AC:

2372

AN:

6496

Middle Eastern (MID)

AF:

0.328

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.391

AC:

12941

AN:

33062

Other (OTH)

AF:

0.335

AC:

1019

AN:

3042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

543

1086

1628

2171

2714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.311

AC:

47072

AN:

151260

Hom.:

8141

Cov.:

AF XY:

0.308

AC XY:

22797

AN XY:

74012

show subpopulations

African (AFR)

AF:

0.179

AC:

7269

AN:

40638

American (AMR)

AF:

0.315

AC:

4805

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1120

AN:

3470

East Asian (EAS)

AF:

0.0777

AC:

402

AN:

5174

South Asian (SAS)

AF:

0.258

AC:

1246

AN:

4828

European-Finnish (FIN)

AF:

0.385

AC:

4079

AN:

10594

Middle Eastern (MID)

AF:

0.349

AC:

102

AN:

292

European-Non Finnish (NFE)

AF:

0.399

AC:

27095

AN:

67962

Other (OTH)

AF:

0.331

AC:

700

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1638

3276

4915

6553

8191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.364

Hom.:

14238

Bravo

AF:

0.298

Asia WGS

AF:

0.182

AC:

636

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

9.7

(source)

DANN

Benign

0.86

PhyloP100

0.99

PromoterAI

0.028

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over