7-100627570-G-A

Variant names:

• chr7-100627570-G-A
• rs41295912
• NM_003227.4:c.1767+7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003227.4(TFR2):​c.1767+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00729 in 1,614,130 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (66 hom.)
• Consequence: TFR2 NM_003227.4 splice_region, intron
• Scores: Splicing: ADA: 0.01185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.228
• 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia

ENSG00000298392 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-100627570-G-A is Benign according to our data. Variant chr7-100627570-G-A is described in ClinVar as Benign. ClinVar VariationId is 415943.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 = 0.00593 (903/152312) while in subpopulation SAS AF = 0.0106 (51/4830). AF 95% confidence interval is 0.00825. There are 6 homozygotes in GnomAd4. There are 412 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	NM_003227.4	MANE Select	c.1767+7C>T		splice_region intron	N/A	NP_003218.2
	TFR2	NM_001206855.3		c.1254+7C>T		splice_region intron	N/A	NP_001193784.1	Q9UP52-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	ENST00000223051.8	TSL:1 MANE Select	c.1767+7C>T		splice_region intron	N/A	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.1863+7C>T		splice_region intron	N/A	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.1767+7C>T		splice_region intron	N/A	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 904 AN: 152194 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00649

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00773

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00703 AC: 1766 AN: 251060 AF XY: 0.00735

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.0303

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00616

Gnomad NFE exome AF: 0.00693

Gnomad OTH exome AF: 0.00849

GnomAD4 exome AF: 0.00743 AC: 10861 AN: 1461818 Hom.: 66 Cov.: 40 AF XY: 0.00767 AC XY: 5575 AN XY: 727200

African (AFR) AF: 0.00137 AC: 46 AN: 33478

American (AMR) AF: 0.00291 AC: 130 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0304 AC: 795 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0130 AC: 1124 AN: 86256

European-Finnish (FIN) AF: 0.00622 AC: 332 AN: 53412

Middle Eastern (MID) AF: 0.0166 AC: 96 AN: 5768

European-Non Finnish (NFE) AF: 0.00702 AC: 7808 AN: 1111964

Other (OTH) AF: 0.00874 AC: 528 AN: 60388

GnomAD4 genome AF: 0.00593 AC: 903 AN: 152312 Hom.: 6 Cov.: 33 AF XY: 0.00553 AC XY: 412 AN XY: 74470

African (AFR) AF: 0.00135 AC: 56 AN: 41570

American (AMR) AF: 0.00405 AC: 62 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4830

European-Finnish (FIN) AF: 0.00649 AC: 69 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00773 AC: 526 AN: 68016

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00734 Hom.: 6

Bravo AF: 0.00497

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00700

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hemochromatosis type 3 (2)
-	-	1	Hereditary hemochromatosis (1)
-	-	1	TFR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.58
PhyloP100		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.020		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: rs41295912; hg19: chr7-100225193;