rs35704760

Variant names:

• chr7-100627489-G-A
• rs35704760
• NM_003227.4:c.1770C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-100627489-G-A
• chr7-100627489-G-C
• chr7-100627489-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003227.4(TFR2):​c.1770C>T​(p.Asp590Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,611,606 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (73 hom.)
• Consequence: TFR2 NM_003227.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -4.30
• Publications: 4 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 -16 ACMG points.

• BP6: Variant 7-100627489-G-A is Benign according to our data. Variant chr7-100627489-G-A is described in ClinVar as Benign. ClinVar VariationId is 21368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00349 (531/152326) while in subpopulation SAS AF = 0.0141 (68/4830). AF 95% confidence interval is 0.0114. There are 11 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.1770C>T	p.Asp590Asp	splice_region synonymous	Exon 16 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.1257C>T	p.Asp419Asp	splice_region 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.1770C>T	p.Asp590Asp	splice_region synonymous	Exon 16 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000431692.5	TSL:5	c.*445C>T		splice_region	Exon 14 of 16	ENSP00000413905.1	E7ET36
	TFR2	ENST00000855275.1		c.1866C>T	p.Asp622Asp	splice_region synonymous	Exon 18 of 20	ENSP00000525334.1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152208 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00671

GnomAD2 exomes AF: 0.00641 AC: 1571 AN: 245126 AF XY: 0.00693

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00468

Gnomad ASJ exome AF: 0.0547

Gnomad EAS exome AF: 0.000332

Gnomad FIN exome AF: 0.000339

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00785

GnomAD4 exome AF: 0.00381 AC: 5559 AN: 1459280 Hom.: 73 Cov.: 40 AF XY: 0.00426 AC XY: 3089 AN XY: 725722

African (AFR) AF: 0.00135 AC: 45 AN: 33438

American (AMR) AF: 0.00433 AC: 191 AN: 44102

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 1376 AN: 26064

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39592

South Asian (SAS) AF: 0.0143 AC: 1231 AN: 85956

European-Finnish (FIN) AF: 0.000282 AC: 15 AN: 53248

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5762

European-Non Finnish (NFE) AF: 0.00197 AC: 2189 AN: 1110818

Other (OTH) AF: 0.00718 AC: 433 AN: 60300

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152326 Hom.: 11 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74488

African (AFR) AF: 0.000914 AC: 38 AN: 41576

American (AMR) AF: 0.00314 AC: 48 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00243 AC: 165 AN: 68026

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00413 Hom.: 11

Bravo AF: 0.00346

Asia WGS AF: 0.00664 AC: 24 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 provided (2)
-	-	1	Hereditary hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.38
DANN	Benign	0.68
PhyloP100		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -31

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

Other links and lift over

dbSNP: rs35704760; hg19: chr7-100225112; COSMIC: COSV56154261; COSMIC: COSV56154261;