rs757050571

Variant names:

• chr7-100631010-G-A
• rs757050571
• NM_003227.4:c.1149C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-100631010-G-A
• chr7-100631010-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_003227.4(TFR2):​c.1149C>T​(p.Ser383Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000774 in 1,523,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: TFR2 NM_003227.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0860
• 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

LOC124901709 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07288703).
• BP6: Variant 7-100631010-G-A is Benign according to our data. Variant chr7-100631010-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 530396.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.086 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	NM_003227.4	MANE Select	c.1149C>T	p.Ser383Ser	synonymous	Exon 9 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.636C>T	p.Ser212Ser	synonymous	Exon 6 of 15	NP_001193784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	ENST00000223051.8	TSL:1 MANE Select	c.1149C>T	p.Ser383Ser	synonymous	Exon 9 of 18	ENSP00000223051.3
	TFR2	ENST00000431692.5	TSL:5	c.892C>T	p.Pro298Ser	missense	Exon 7 of 16	ENSP00000413905.1
	TFR2	ENST00000462107.1	TSL:5	c.1149C>T	p.Ser383Ser	synonymous	Exon 10 of 19	ENSP00000420525.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000730 AC: 9 AN: 123224 AF XY: 0.0000777

Gnomad AFR exome AF: 0.000277

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000108

Gnomad NFE exome AF: 0.0000938

Gnomad OTH exome AF: 0.000272

GnomAD4 exome AF: 0.0000802 AC: 110 AN: 1371686 Hom.: 0 Cov.: 31 AF XY: 0.0000846 AC XY: 57 AN XY: 673790

African (AFR) AF: 0.0000320 AC: 1 AN: 31242

American (AMR) AF: 0.00 AC: 0 AN: 32972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21950

East Asian (EAS) AF: 0.00 AC: 0 AN: 36478

South Asian (SAS) AF: 0.00 AC: 0 AN: 69972

European-Finnish (FIN) AF: 0.0000460 AC: 2 AN: 43500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 0.0000977 AC: 105 AN: 1074312

Other (OTH) AF: 0.0000349 AC: 2 AN: 57276

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000268 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	6.1
DANN	Uncertain	0.99
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.086
PROVEAN	Benign	0.30	N
REVEL	Benign	0.0080
Sift	Benign	0.063	T
Sift4G	Pathogenic	0.0	D
Vest4		0.32
MutPred		0.31		Gain of phosphorylation at P298 (P = 0.006)
MVP		0.56
ClinPred		0.042	T
GERP RS		-1.1
Mutation Taster		=96/4	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: rs757050571; hg19: chr7-100228633;