chr3-133756943-T-C

Variant names:

• chr3-133756943-T-C
• rs8177232
• NM_001063.4:c.804T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001063.4(TF):​c.804T>C​(p.His268His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,086 control chromosomes in the GnomAD database, including 1,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (714 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (655 hom.)
• Consequence: TF NM_001063.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.54
• Publications: 5 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, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-133756943-T-C is Benign according to our data. Variant chr3-133756943-T-C is described in ClinVar as Benign. ClinVar VariationId is 343440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001063.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TF	NM_001063.4	MANE Select	c.804T>C	p.His268His	synonymous	Exon 7 of 17	NP_001054.2	P02787
	TF	NM_001354703.2		c.672T>C	p.His224His	synonymous	Exon 13 of 23	NP_001341632.2
	TF	NM_001354704.2		c.423T>C	p.His141His	synonymous	Exon 6 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.804T>C	p.His268His	synonymous	Exon 7 of 17	ENSP00000385834.3	P02787
	TF	ENST00000877249.1		c.156T>C	p.His52His	synonymous	Exon 2 of 12	ENSP00000547308.1
	TF	ENST00000877246.1		c.217-7239T>C		intron	N/A	ENSP00000547305.1

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 8191 AN: 152130 Hom.: 712 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0142 AC: 3566 AN: 251434 AF XY: 0.0102

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.00968

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00558 AC: 8164 AN: 1461838 Hom.: 655 Cov.: 33 AF XY: 0.00483 AC XY: 3509 AN XY: 727218

African (AFR) AF: 0.193 AC: 6458 AN: 33480

American (AMR) AF: 0.0111 AC: 496 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00884 AC: 51 AN: 5768

European-Non Finnish (NFE) AF: 0.000335 AC: 373 AN: 1111970

Other (OTH) AF: 0.0124 AC: 747 AN: 60392

GnomAD4 genome AF: 0.0539 AC: 8203 AN: 152248 Hom.: 714 Cov.: 32 AF XY: 0.0523 AC XY: 3897 AN XY: 74452

African (AFR) AF: 0.186 AC: 7740 AN: 41522

American (AMR) AF: 0.0216 AC: 331 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68018

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.0277 Hom.: 331

Bravo AF: 0.0611

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.55
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs8177232; hg19: chr3-133475787;