rs80338876

Variant names:

• chr7-100641198-C-G
• rs80338876
• NM_003227.4:c.64G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-100641198-C-G
• chr7-100641198-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003227.4(TFR2):​c.64G>C​(p.Val22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,380,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.717

Genes affected

TFR2 (HGNC:11762): (transferrin receptor 2) This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2128497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4	c.64G>C	p.Val22Leu	missense_variant	Exon 2 of 18	ENST00000223051.8	NP_003218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.64G>C	p.Val22Leu	missense_variant	Exon 2 of 18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1380386 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 678456

African (AFR) AF: 0.00 AC: 0 AN: 31404

American (AMR) AF: 0.00 AC: 0 AN: 33086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23588

East Asian (EAS) AF: 0.00 AC: 0 AN: 36060

South Asian (SAS) AF: 0.00 AC: 0 AN: 76018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069106

Other (OTH) AF: 0.0000174 AC: 1 AN: 57314

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.052	T;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	T;T;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N
PhyloP100		0.72
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.33	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.030	D;D;D
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0070	B;.;B
Vest4		0.26
MutPred		0.26		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.51
MPC		0.33
ClinPred		0.13	T
GERP RS		3.3
PromoterAI		-0.037	Neutral
Varity_R		0.052
gMVP		0.35
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80338876; hg19: chr7-100238821;