chr3-133746376-G-C

Variant names:

• chr3-133746376-G-C
• rs41298275
• NM_001354703.2:c.-89-2036G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001354703.2(TF):​c.-89-2036G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,541,924 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (12 hom.)
• Consequence: TF NM_001354703.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 2 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

ENSG00000291042 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-133746376-G-C is Benign according to our data. Variant chr3-133746376-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 343421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00569 (867/152370) while in subpopulation AFR AF = 0.0199 (826/41602). AF 95% confidence interval is 0.0187. There are 6 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354703.2. 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_001354703.2		c.-89-2036G>C		intron	N/A	NP_001341632.2
	TF	NM_001063.4	MANE Select	c.-65G>C		upstream_gene	N/A	NP_001054.2	P02787
	TF	NM_001354704.2		c.-273G>C		upstream_gene	N/A	NP_001341633.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TF	ENST00000466911.5	TSL:4	c.-90+127G>C		intron	N/A	ENSP00000417468.1	C9JB55
	TF	ENST00000474287.5	TSL:2	n.49G>C		non_coding_transcript_exon	Exon 1 of 3
	ENSG00000291042	ENST00000460564.5	TSL:4	n.382-7219G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 868 AN: 152252 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000621 AC: 863 AN: 1389554 Hom.: 12 Cov.: 27 AF XY: 0.000550 AC XY: 378 AN XY: 687758

African (AFR) AF: 0.0226 AC: 714 AN: 31604

American (AMR) AF: 0.000869 AC: 32 AN: 36806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36082

South Asian (SAS) AF: 0.000113 AC: 9 AN: 79516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43204

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5560

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1073612

Other (OTH) AF: 0.00157 AC: 91 AN: 57942

GnomAD4 genome AF: 0.00569 AC: 867 AN: 152370 Hom.: 6 Cov.: 33 AF XY: 0.00535 AC XY: 399 AN XY: 74512

African (AFR) AF: 0.0199 AC: 826 AN: 41602

American (AMR) AF: 0.00176 AC: 27 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00402 Hom.: 1

Bravo AF: 0.00632

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.13
DANN	Benign	0.74
PhyloP100		-1.4
PromoterAI		0.12	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41298275; hg19: chr3-133465220;