rs150303632

Positions:

• chr7-100626814-C-G
• chr7-100626814-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003227.4(TFR2):​c.2085G>C​(p.Ser695Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00803 in 1,549,264 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (52 hom.)
• Consequence: TFR2 NM_003227.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.75

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 7-100626814-C-G is Benign according to our data. Variant chr7-100626814-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 220387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00738 (1124/152308) while in subpopulation NFE AF= 0.0104 (709/68024). AF 95% confidence interval is 0.00979. There are 7 homozygotes in gnomad4. There are 567 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFR2	NM_003227.4	c.2085G>C	p.Ser695Ser	synonymous_variant	17/18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3	c.1572G>C	p.Ser524Ser	synonymous_variant	14/15		NP_001193784.1
LOC124901709	XR_007060454.1	n.433+4260C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.2085G>C	p.Ser695Ser	synonymous_variant	17/18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152190 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00669 AC: 1033 AN: 154310 Hom.: 8 AF XY: 0.00672 AC XY: 547 AN XY: 81438

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.00963

Gnomad OTH exome AF: 0.00794

GnomAD4 exome AF: 0.00810 AC: 11310 AN: 1396956 Hom.: 52 Cov.: 36 AF XY: 0.00810 AC XY: 5580 AN XY: 689134

Gnomad4 AFR exome AF: 0.00101

Gnomad4 AMR exome AF: 0.00384

Gnomad4 ASJ exome AF: 0.00461

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.0189

Gnomad4 NFE exome AF: 0.00898

Gnomad4 OTH exome AF: 0.00576

GnomAD4 genome AF: 0.00738 AC: 1124 AN: 152308 Hom.: 7 Cov.: 33 AF XY: 0.00761 AC XY: 567 AN XY: 74468

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00805 Hom.: 3

Bravo AF: 0.00581

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TFR2: BP4, BP7, BS2 -

Hemochromatosis type 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary hemochromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.030
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs150303632; hg19: chr7-100224437; COSMIC: COSV56155234; COSMIC: COSV56155234;