7-100631010-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003227.4(TFR2):​c.1149C>G​(p.Ser383Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 1,371,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S383S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000066 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014428109).

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>G	p.Ser383Arg	missense	Exon 9 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.636C>G	p.Ser212Arg	missense	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>G	p.Ser383Arg	missense	Exon 9 of 18	ENSP00000223051.3
	TFR2	ENST00000462107.1	TSL:5	c.1149C>G	p.Ser383Arg	missense	Exon 10 of 19	ENSP00000420525.1
	TFR2	ENST00000431692.5	TSL:5	c.892C>G	p.Pro298Ala	missense	Exon 7 of 16	ENSP00000413905.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152128 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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000325 AC: 4 AN: 123224 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000189

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000656 AC: 9 AN: 1371664 Hom.: 0 Cov.: 31 AF XY: 0.00000742 AC XY: 5 AN XY: 673774

African (AFR) AF: 0.00 AC: 0 AN: 31242

American (AMR) AF: 0.000182 AC: 6 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: 69964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3982

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1074302

Other (OTH) AF: 0.00 AC: 0 AN: 57276

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 AN: 67962

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000894 AC: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.0
DANN	Benign	0.95
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.086
PROVEAN	Benign	0.90	N
REVEL	Benign	0.028
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Vest4		0.35
MutPred		0.28		Loss of catalytic residue at P298 (P = 0.012)
MVP		0.24
ClinPred		0.035	T
GERP RS		-1.1
Varity_R		0.058
Mutation Taster		=297/3	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; COSMIC: COSV56152887; COSMIC: COSV56152887;