NM_003227.4:c.1941G>T

Variant names:

• chr7-100627318-C-A
• rs111760099
• NM_003227.4:c.1941G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.391
• 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

LOC124901709 (HGNC:):

ACMG classification

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

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.1941G>T	p.Gly647Gly	synonymous	Exon 16 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.1428G>T	p.Gly476Gly	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.1941G>T	p.Gly647Gly	synonymous	Exon 16 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.2037G>T	p.Gly679Gly	synonymous	Exon 18 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.1941G>T	p.Gly647Gly	synonymous	Exon 17 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 633 AN: 152206 Hom.: 3 Cov.: 33

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

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.: 3 Cov.: 35 AF XY: 0.00129 AC XY: 888 AN XY: 689504

African (AFR) AF: 0.0134 AC: 424 AN: 31572

American (AMR) AF: 0.00190 AC: 68 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.000119 AC: 3 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35748

South Asian (SAS) AF: 0.000278 AC: 22 AN: 79204

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48872

Middle Eastern (MID) AF: 0.00523 AC: 25 AN: 4776

European-Non Finnish (NFE) AF: 0.00108 AC: 1162 AN: 1078918

Other (OTH) AF: 0.00162 AC: 94 AN: 57882

GnomAD4 genome AF: 0.00415 AC: 632 AN: 152324 Hom.: 3 Cov.: 33 AF XY: 0.00377 AC XY: 281 AN XY: 74474

African (AFR) AF: 0.0126 AC: 522 AN: 41572

American (AMR) AF: 0.00229 AC: 35 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00455

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.8
DANN	Benign	0.90
PhyloP100		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs111760099; hg19: chr7-100224941; COSMIC: COSV99774828; COSMIC: COSV99774828;