7-100627488-C-T

Position:

• chr7-100627488-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003227.4(TFR2):​c.1771G>A​(p.Asp591Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.898

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]

TFR2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06775245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFR2	NM_003227.4	c.1771G>A	p.Asp591Asn	missense_variant	16/18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3	c.1258G>A	p.Asp420Asn	missense_variant	13/15		NP_001193784.1
LOC124901709	XR_007060454.1	n.434-3668C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.1771G>A	p.Asp591Asn	missense_variant	16/18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458792 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 725436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.62	T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.12	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.53	N;N
REVEL	Benign	0.066
Sift	Benign	0.57	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.56	P;P
Vest4		0.056
MutPred		0.45		Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);
MVP		0.38
MPC		0.32
ClinPred		0.098	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1060502723; hg19: chr7-100225111; COSMIC: COSV56156482; COSMIC: COSV56156482;