rs8177233

Variant names:

• chr3-133757117-A-G
• rs8177233
• NM_001063.4:c.870+108A>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_001063.4(TF):c.870+108A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0131 (AC=18,691) in the gnomAD database across 1,427,962 control chromosomes, including 1,902 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.229. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars).

• Frequency:
  • Genomes: 𝑓 0.065 (1041 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (861 hom.)
• Consequence: TF NM_001063.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59
• Publications: 1 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, ClinGen, Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2289 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TF	NM_001063.4	MANE Select	c.870+108A>G		intron	N/A	NP_001054.2	P02787
	TF	NM_001354703.2		c.738+108A>G		intron	N/A	NP_001341632.2
	TF	NM_001354704.2		c.489+108A>G		intron	N/A	NP_001341633.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TF	ENST00000402696.9	TSL:1 MANE Select	c.870+108A>G		intron	N/A	ENSP00000385834.3	P02787
	TF	ENST00000877249.1		c.222+108A>G		intron	N/A	ENSP00000547308.1	A0ACI8QAC3
	TF	ENST00000877246.1		c.217-7065A>G		intron	N/A	ENSP00000547305.1	A0ACI8R955

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0650	AC:9889	Hom:1039	AN:152038	Cov:32
GnomAD4 exome	AF: 0.00688	AC:8782	Hom:861	AN:1275806	Cov:
GnomAD4 genome	AF: 0.0651	AC:9909	Hom:1041	AN:152156	Cov:32
TOPMed (Bravo)	AF: 0.0745	AC:19716	Hom:2081	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0490	AC:2350	Hom:271	AN:47938	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0491	AC:115	Hom:5	AN:2342	Cov:
GenomeAsia100K	AF: 0.0130	AC:48	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.0455	AC:8	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122720	Cov:
Turkish Variome	AF: 0.000647	AC:1	Hom:0	AN:1546	Cov:
UK10K	AF: 0.000397	AC:3	Hom:	AN:7562	Cov:

Showing 11 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00192	126	65728	0.00135	173	127892

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.2
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.81
GPN-Star LLR	N/A	-0.76
GPN-Star score	N/A	0.76
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	3.6

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs8177233;

hg19: chr3-133475961;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar