chr7-100627318-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_003227.4(TFR2):c.1941G>T(p.Gly647Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,550,162 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G647G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0041 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

TFR2
NM_003227.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.391

Publications

2 publications found

Variant links:

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

TFR2 links:

LOC124901709 (HGNC:):

LOC124901709 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 7-100627318-C-A is Benign according to our data. Variant chr7-100627318-C-A is described in ClinVar as Benign. ClinVar VariationId is 530400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.391 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00415 (632/152324) while in subpopulation AFR AF = 0.0126 (522/41572). AF 95% confidence interval is 0.0117. There are 3 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TFR2	NM_003227.4 link	c.1941G>T	p.Gly647Gly	synonymous_variant	Exon 16 of 18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3 link	c.1428G>T	p.Gly476Gly	synonymous_variant	Exon 13 of 15		NP_001193784.1
LOC124901709	XR_007060454.1 link	n.434-3838C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.1941G>T	p.Gly647Gly	synonymous_variant	Exon 16 of 18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

633

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00141

AC:

217

AN:

153774

AF XY:

0.00122

show subpopulations

Gnomad AFR exome

AF:

0.0139

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000671

Gnomad NFE exome

AF:

0.000679

Gnomad OTH exome

AF:

0.00160

GnomAD4 exome

AF:

0.00129

AC:

1799

AN:

1397838

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

888

AN XY:

689504

show subpopulations

African (AFR)

AF:

0.0134

AC:

424

AN:

31572

American (AMR)

AF:

0.00190

AC:

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.000119

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

35748

South Asian (SAS)

AF:

0.000278

AC:

AN:

79204

European-Finnish (FIN)

AF:

0.0000205

AC:

AN:

48872

Middle Eastern (MID)

AF:

0.00523

AC:

AN:

4776

European-Non Finnish (NFE)

AF:

0.00108

AC:

1162

AN:

1078918

Other (OTH)

AF:

0.00162

AC:

AN:

57882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

130

260

391

521

651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00415

AC:

632

AN:

152324

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0126

AC:

522

AN:

41572

American (AMR)

AF:

0.00229

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

68026

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00455

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Hereditary hemochromatosis

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

9.8

(source)

DANN

Benign

0.90

PhyloP100

-0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over