chr7-100628248-G-A

Variant names:

• chr7-100628248-G-A
• rs41295899
• NM_003227.4:c.1449C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003227.4(TFR2):​c.1449C>T​(p.Ser483Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,602,130 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (9 hom., cov: 31)
  • Exomes 𝑓: 0.00059 (5 hom.)
• Consequence: TFR2 NM_003227.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.334
• Publications: 1 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

ENSG00000298392 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 7-100628248-G-A is Benign according to our data. Variant chr7-100628248-G-A is described in ClinVar as Benign. ClinVar VariationId is 258986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.334 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00615 (900/146274) while in subpopulation AFR AF = 0.0208 (820/39462). AF 95% confidence interval is 0.0196. There are 9 homozygotes in GnomAd4. There are 430 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1449C>T	p.Ser483Ser	synonymous	Exon 11 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.936C>T	p.Ser312Ser	synonymous	Exon 8 of 15	NP_001193784.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	ENST00000223051.8	TSL:1 MANE Select	c.1449C>T	p.Ser483Ser	synonymous	Exon 11 of 18	ENSP00000223051.3
	TFR2	ENST00000855275.1		c.1545C>T	p.Ser515Ser	synonymous	Exon 13 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.1449C>T	p.Ser483Ser	synonymous	Exon 12 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.00615 AC: 899 AN: 146182 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00396

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0000894

Gnomad OTH AF: 0.00845

GnomAD2 exomes AF: 0.00147 AC: 369 AN: 251390 AF XY: 0.00102

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000593 AC: 864 AN: 1455856 Hom.: 5 Cov.: 39 AF XY: 0.000507 AC XY: 367 AN XY: 724226

African (AFR) AF: 0.0209 AC: 696 AN: 33296

American (AMR) AF: 0.00117 AC: 52 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52814

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5724

European-Non Finnish (NFE) AF: 0.0000307 AC: 34 AN: 1108112

Other (OTH) AF: 0.00130 AC: 78 AN: 59978

GnomAD4 genome AF: 0.00615 AC: 900 AN: 146274 Hom.: 9 Cov.: 31 AF XY: 0.00607 AC XY: 430 AN XY: 70866

African (AFR) AF: 0.0208 AC: 820 AN: 39462

American (AMR) AF: 0.00395 AC: 56 AN: 14162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 4796

South Asian (SAS) AF: 0.00 AC: 0 AN: 4546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9556

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.0000894 AC: 6 AN: 67106

Other (OTH) AF: 0.00837 AC: 17 AN: 2030

Alfa AF: 0.00296 Hom.: 4

Bravo AF: 0.00644

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.3
DANN	Benign	0.86
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41295899; hg19: chr7-100225871; COSMIC: COSV56153937; COSMIC: COSV56153937;