7-100626814-C-G

Variant names:

• chr7-100626814-C-G
• rs150303632
• NM_003227.4:c.2085G>C

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.2085G>C​(p.Ser695Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00803 in 1,549,264 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S695S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0074 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (52 hom.)
• Consequence: TFR2 NM_003227.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.75
• Publications: 3 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=-0.72).
• BP6: Variant 7-100626814-C-G is Benign according to our data. Variant chr7-100626814-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00738 (1124/152308) while in subpopulation NFE AF = 0.0104 (709/68024). AF 95% confidence interval is 0.00979. There are 7 homozygotes in GnomAd4. There are 567 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2085G>C	p.Ser695Ser	synonymous	Exon 17 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.1572G>C	p.Ser524Ser	synonymous	Exon 14 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.2085G>C	p.Ser695Ser	synonymous	Exon 17 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.2181G>C	p.Ser727Ser	synonymous	Exon 19 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.2085G>C	p.Ser695Ser	synonymous	Exon 18 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152190 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00669 AC: 1033 AN: 154310 AF XY: 0.00672

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.00963

Gnomad OTH exome AF: 0.00794

GnomAD4 exome AF: 0.00810 AC: 11310 AN: 1396956 Hom.: 52 Cov.: 36 AF XY: 0.00810 AC XY: 5580 AN XY: 689134

African (AFR) AF: 0.00101 AC: 32 AN: 31588

American (AMR) AF: 0.00384 AC: 137 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 116 AN: 25168

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35730

South Asian (SAS) AF: 0.00125 AC: 99 AN: 79220

European-Finnish (FIN) AF: 0.0189 AC: 892 AN: 47168

Middle Eastern (MID) AF: 0.00199 AC: 11 AN: 5514

European-Non Finnish (NFE) AF: 0.00898 AC: 9687 AN: 1078906

Other (OTH) AF: 0.00576 AC: 334 AN: 57958

GnomAD4 genome AF: 0.00738 AC: 1124 AN: 152308 Hom.: 7 Cov.: 33 AF XY: 0.00761 AC XY: 567 AN XY: 74468

African (AFR) AF: 0.000986 AC: 41 AN: 41572

American (AMR) AF: 0.00719 AC: 110 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0104 AC: 709 AN: 68024

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

Alfa AF: 0.00805 Hom.: 3

Bravo AF: 0.00581

Asia WGS AF: 0.00173 AC: 6 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	-0.72
CADD	Benign	0.030
DANN	Benign	0.59
PhyloP100		-4.8
Mutation Taster		=98/2	polymorphism

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: rs150303632; hg19: chr7-100224437; COSMIC: COSV56155234; COSMIC: COSV56155234;