chr3-196062543-T-C

Variant names:

• chr3-196062543-T-C
• rs2239641
• NM_001128148.3:c.1468+39A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001128148.3(TFRC):​c.1468+39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,574,680 control chromosomes in the GnomAD database, including 264,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (19438 hom., cov: 33)
  • Exomes 𝑓: 0.58 (244830 hom.)
• Consequence: TFRC NM_001128148.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.500
• Publications: 7 publications found

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: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-196062543-T-C is Benign according to our data. Variant chr3-196062543-T-C is described in ClinVar as Benign. ClinVar VariationId is 1273355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.603 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFRC	NM_001128148.3	MANE Select	c.1468+39A>G		intron	N/A	NP_001121620.1
	TFRC	NM_003234.4		c.1468+39A>G		intron	N/A	NP_003225.2
	TFRC	NM_001313965.2		c.1225+39A>G		intron	N/A	NP_001300894.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFRC	ENST00000360110.9	TSL:1 MANE Select	c.1468+39A>G		intron	N/A	ENSP00000353224.4
	TFRC	ENST00000392396.7	TSL:1	c.1468+39A>G		intron	N/A	ENSP00000376197.3
	TFRC	ENST00000420415.5	TSL:1	c.1225+39A>G		intron	N/A	ENSP00000390133.1

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73313 AN: 152050 Hom.: 19441 Cov.: 33

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.608

Gnomad OTH AF: 0.521

GnomAD2 exomes AF: 0.503 AC: 119475 AN: 237402 AF XY: 0.515

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.566

Gnomad NFE exome AF: 0.606

Gnomad OTH exome AF: 0.545

GnomAD4 exome AF: 0.578 AC: 822548 AN: 1422512 Hom.: 244830 Cov.: 24 AF XY: 0.578 AC XY: 410071 AN XY: 709408

African (AFR) AF: 0.283 AC: 9046 AN: 32004

American (AMR) AF: 0.380 AC: 15193 AN: 39984

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 13915 AN: 25470

East Asian (EAS) AF: 0.200 AC: 7908 AN: 39528

South Asian (SAS) AF: 0.527 AC: 43649 AN: 82804

European-Finnish (FIN) AF: 0.560 AC: 29794 AN: 53180

Middle Eastern (MID) AF: 0.663 AC: 3712 AN: 5602

European-Non Finnish (NFE) AF: 0.614 AC: 666400 AN: 1084932

Other (OTH) AF: 0.558 AC: 32931 AN: 59008

GnomAD4 genome AF: 0.482 AC: 73322 AN: 152168 Hom.: 19438 Cov.: 33 AF XY: 0.478 AC XY: 35541 AN XY: 74386

African (AFR) AF: 0.294 AC: 12204 AN: 41512

American (AMR) AF: 0.449 AC: 6869 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1933 AN: 3472

East Asian (EAS) AF: 0.166 AC: 862 AN: 5182

South Asian (SAS) AF: 0.514 AC: 2478 AN: 4824

European-Finnish (FIN) AF: 0.569 AC: 6014 AN: 10578

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.608 AC: 41344 AN: 67990

Other (OTH) AF: 0.515 AC: 1089 AN: 2116

Alfa AF: 0.551 Hom.: 7973

Bravo AF: 0.460

Asia WGS AF: 0.363 AC: 1265 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	TFRC-related combined immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.1
DANN	Benign	0.66
PhyloP100		0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2239641; hg19: chr3-195789414; COSMIC: COSV64054884; COSMIC: COSV64054884;