rs35704760

Positions:

• chr7-100627489-G-A
• chr7-100627489-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003227.4(TFR2):​c.1770C>T​(p.Asp590=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,611,606 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (73 hom.)
• Consequence: TFR2 NM_003227.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -4.30

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]

LOC124901709 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 7-100627489-G-A is Benign according to our data. Variant chr7-100627489-G-A is described in ClinVar as [Benign]. Clinvar id is 21368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00349 (531/152326) while in subpopulation SAS AF= 0.0141 (68/4830). AF 95% confidence interval is 0.0114. There are 11 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFR2	NM_003227.4	c.1770C>T	p.Asp590=	splice_region_variant, synonymous_variant	16/18	ENST00000223051.8
LOC124901709	XR_007060454.1	n.434-3667G>A		intron_variant, non_coding_transcript_variant
TFR2	NM_001206855.3	c.1257C>T	p.Asp419=	splice_region_variant, synonymous_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.1770C>T	p.Asp590=	splice_region_variant, synonymous_variant	16/18	1	NM_003227.4	P1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152208 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00671

GnomAD3 exomes AF: 0.00641 AC: 1571 AN: 245126 Hom.: 29 AF XY: 0.00693 AC XY: 919 AN XY: 132632

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00468

Gnomad ASJ exome AF: 0.0547

Gnomad EAS exome AF: 0.000332

Gnomad SAS exome AF: 0.0145

Gnomad FIN exome AF: 0.000339

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00785

GnomAD4 exome AF: 0.00381 AC: 5559 AN: 1459280 Hom.: 73 Cov.: 40 AF XY: 0.00426 AC XY: 3089 AN XY: 725722

Gnomad4 AFR exome AF: 0.00135

Gnomad4 AMR exome AF: 0.00433

Gnomad4 ASJ exome AF: 0.0528

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0143

Gnomad4 FIN exome AF: 0.000282

Gnomad4 NFE exome AF: 0.00197

Gnomad4 OTH exome AF: 0.00718

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152326 Hom.: 11 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74488

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.0527

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00443 Hom.: 10

Bravo AF: 0.00346

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 3 Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hereditary hemochromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

TFR2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.38
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -31

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

Publications

LitVar

Other links and lift over

dbSNP: rs35704760; hg19: chr7-100225112; COSMIC: COSV56154261; COSMIC: COSV56154261;