3-133777188-G-A

Variant names:

• chr3-133777188-G-A
• rs121918677
• NM_001063.4:c.2012G>A

Variant summary

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

The NM_001063.4(TF):​c.2012G>A​(p.Gly671Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00385 in 1,614,010 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (14 hom.)
• Consequence: TF NM_001063.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 5.21
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01994747).
• BP6: Variant 3-133777188-G-A is Benign according to our data. Variant chr3-133777188-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 12616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00294 (448/152282) while in subpopulation NFE AF = 0.00507 (345/68016). AF 95% confidence interval is 0.00463. There are 3 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.2012G>A	p.Gly671Glu	missense	Exon 16 of 17	NP_001054.2	P02787
	TF	NM_001354703.2		c.1880G>A	p.Gly627Glu	missense	Exon 22 of 23	NP_001341632.2
	TF	NM_001354704.2		c.1631G>A	p.Gly544Glu	missense	Exon 15 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.2012G>A	p.Gly671Glu	missense	Exon 16 of 17	ENSP00000385834.3	P02787
	TF	ENST00000467842.1	TSL:1	n.3006G>A		non_coding_transcript_exon	Exon 2 of 2
	TF	ENST00000877249.1		c.1364G>A	p.Gly455Glu	missense	Exon 11 of 12	ENSP00000547308.1

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 448 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00507

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00251 AC: 630 AN: 251236 AF XY: 0.00260

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000745

Gnomad NFE exome AF: 0.00429

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00395 AC: 5772 AN: 1461728 Hom.: 14 Cov.: 31 AF XY: 0.00387 AC XY: 2813 AN XY: 727192

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00201 AC: 90 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.000788 AC: 42 AN: 53274

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00485 AC: 5397 AN: 1111996

Other (OTH) AF: 0.00286 AC: 173 AN: 60396

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00255 AC XY: 190 AN XY: 74472

African (AFR) AF: 0.00101 AC: 42 AN: 41544

American (AMR) AF: 0.00176 AC: 27 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00507 AC: 345 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00394 Hom.: 3

Bravo AF: 0.00275

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00250 AC: 303

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00462

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Atransferrinemia (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	TF-related disorder (1)
1	-	-	Transferrin variant B2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.042	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		5.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.63
MVP		0.86
MPC		1.2
ClinPred		0.15	T
GERP RS		5.5
Varity_R		0.94
gMVP		0.83
Mutation Taster		=23/77	disease causing

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: rs121918677; hg19: chr3-133496032;