rs41296648

Variant names:

• chr7-100620741-G-A
• rs41296648
• NM_003227.4:c.*116C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_003227.4(TFR2):​c.*116C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,447,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: TFR2 NM_003227.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.783
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• hemochromatosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-100620741-G-A is Benign according to our data. Variant chr7-100620741-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 358282.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00219 (334/152316) while in subpopulation AFR AF = 0.0077 (320/41572). AF 95% confidence interval is 0.007. There are 0 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4	c.*116C>T		3_prime_UTR_variant	Exon 18 of 18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3	c.*116C>T		3_prime_UTR_variant	Exon 15 of 15		NP_001193784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.*116C>T		3_prime_UTR_variant	Exon 18 of 18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000265 AC: 343 AN: 1295276 Hom.: 1 Cov.: 19 AF XY: 0.000235 AC XY: 151 AN XY: 642478

African (AFR) AF: 0.00998 AC: 299 AN: 29958

American (AMR) AF: 0.000277 AC: 11 AN: 39726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22726

East Asian (EAS) AF: 0.00 AC: 0 AN: 37480

South Asian (SAS) AF: 0.00 AC: 0 AN: 75700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51072

Middle Eastern (MID) AF: 0.000199 AC: 1 AN: 5018

European-Non Finnish (NFE) AF: 0.00000204 AC: 2 AN: 979316

Other (OTH) AF: 0.000553 AC: 30 AN: 54280

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152316 Hom.: 0 Cov.: 31 AF XY: 0.00228 AC XY: 170 AN XY: 74466

African (AFR) AF: 0.00770 AC: 320 AN: 41572

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00214 Hom.: 0

Bravo AF: 0.00274

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemochromatosis type 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.8
DANN	Benign	0.68
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs41296648; hg19: chr7-100218364;