rs2075674

Variant names:

• chr7-100627408-G-A
• rs2075674
• NM_003227.4:c.1851C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-100627408-G-A
• chr7-100627408-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003227.4(TFR2):​c.1851C>T​(p.Ala617Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,568,136 control chromosomes in the GnomAD database, including 29,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2223 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26810 hom.)
• Consequence: TFR2 NM_003227.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -1.56
• Publications: 34 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

LOC124901709 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 7-100627408-G-A is Benign according to our data. Variant chr7-100627408-G-A is described in ClinVar as Benign. ClinVar VariationId is 21369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

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.1851C>T	p.Ala617Ala	synonymous	Exon 16 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.1338C>T	p.Ala446Ala	synonymous	Exon 13 of 15	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.1851C>T	p.Ala617Ala	synonymous	Exon 16 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.1947C>T	p.Ala649Ala	synonymous	Exon 18 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.1851C>T	p.Ala617Ala	synonymous	Exon 17 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24633 AN: 152140 Hom.: 2220 Cov.: 33

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.176 AC: 31394 AN: 178406 AF XY: 0.176

Gnomad AFR exome AF: 0.0901

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.191 AC: 269930 AN: 1415878 Hom.: 26810 Cov.: 59 AF XY: 0.190 AC XY: 132885 AN XY: 700108

African (AFR) AF: 0.0815 AC: 2650 AN: 32526

American (AMR) AF: 0.163 AC: 6016 AN: 36958

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4696 AN: 25338

East Asian (EAS) AF: 0.112 AC: 4152 AN: 37206

South Asian (SAS) AF: 0.135 AC: 10933 AN: 80878

European-Finnish (FIN) AF: 0.214 AC: 10703 AN: 50100

Middle Eastern (MID) AF: 0.150 AC: 855 AN: 5710

European-Non Finnish (NFE) AF: 0.201 AC: 219261 AN: 1088450

Other (OTH) AF: 0.182 AC: 10664 AN: 58712

GnomAD4 genome AF: 0.162 AC: 24645 AN: 152258 Hom.: 2223 Cov.: 33 AF XY: 0.159 AC XY: 11862 AN XY: 74442

African (AFR) AF: 0.0890 AC: 3699 AN: 41572

American (AMR) AF: 0.153 AC: 2344 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 641 AN: 3470

East Asian (EAS) AF: 0.120 AC: 618 AN: 5170

South Asian (SAS) AF: 0.126 AC: 609 AN: 4832

European-Finnish (FIN) AF: 0.221 AC: 2348 AN: 10604

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13839 AN: 67990

Other (OTH) AF: 0.154 AC: 326 AN: 2116

Alfa AF: 0.186 Hom.: 3999

Bravo AF: 0.155

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hemochromatosis type 3 (3)
-	-	2	not specified (2)
-	-	1	Hereditary hemochromatosis (1)
-	-	1	Hereditary hemochromatosis type 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.9
DANN	Benign	0.87
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2075674; hg19: chr7-100225031; COSMIC: COSV56152969; COSMIC: COSV56152969;