rs41295921

Positions:

• chr7-100627255-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003227.4(TFR2):​c.1995+9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,548,962 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (5 hom.)
• Consequence: TFR2 NM_003227.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.336

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 7-100627255-C-G is Benign according to our data. Variant chr7-100627255-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221011.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr7-100627255-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00204 (310/152322) while in subpopulation NFE AF= 0.00341 (232/68018). AF 95% confidence interval is 0.00305. There are 0 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFR2	NM_003227.4	c.1995+9G>C		intron_variant		ENST00000223051.8
LOC124901709	XR_007060454.1	n.434-3901C>G		intron_variant, non_coding_transcript_variant
TFR2	NM_001206855.3	c.1482+9G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.1995+9G>C		intron_variant		1	NM_003227.4	P1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00182 AC: 273 AN: 150184 Hom.: 1 AF XY: 0.00175 AC XY: 140 AN XY: 79900

Gnomad AFR exome AF: 0.000624

Gnomad AMR exome AF: 0.000364

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000659

Gnomad FIN exome AF: 0.00320

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00315 AC: 4399 AN: 1396640 Hom.: 5 Cov.: 34 AF XY: 0.00307 AC XY: 2113 AN XY: 688870

Gnomad4 AFR exome AF: 0.000381

Gnomad4 AMR exome AF: 0.000420

Gnomad4 ASJ exome AF: 0.000119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000543

Gnomad4 FIN exome AF: 0.00385

Gnomad4 NFE exome AF: 0.00372

Gnomad4 OTH exome AF: 0.00218

GnomAD4 genome AF: 0.00204 AC: 310 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00187 AC XY: 139 AN XY: 74476

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00341

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00261 Hom.: 1

Bravo AF: 0.00157

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hemochromatosis type 3 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Hereditary hemochromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.0
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs41295921; hg19: chr7-100224878;