rs2543519

Variant names:

• chr22-37084229-A-C
• rs2543519
• ENST00000442782.7:c.1262T>G

Your query was ambiguous. Multiple possible variants found:

• chr22-37084229-A-C
• chr22-37084229-A-G
• chr22-37084229-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000442782.7(TMPRSS6):​c.1262T>G​(p.Ile421Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,331,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I421T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 29)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: TMPRSS6 ENST00000442782.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.812
• Publications: 17 publications found

Genes affected

TMPRSS6 (HGNC:16517): (transmembrane serine protease 6) The protein encoded by this gene is a type II transmembrane serine proteinase that is found attached to the cell surface. The encoded protein may be involved in matrix remodeling processes in the liver. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMPRSS6 Gene-Disease associations (from GenCC):

• IRIDA syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16233185).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000442782.7. 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
	TMPRSS6	NM_001374504.1	MANE Select	c.1196+66T>G		intron	N/A	NP_001361433.1
	TMPRSS6	NM_001289000.2		c.1196+66T>G		intron	N/A	NP_001275929.1
	TMPRSS6	NM_001289001.2		c.1196+66T>G		intron	N/A	NP_001275930.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000442782.7	TSL:1	c.1262T>G	p.Ile421Arg	missense	Exon 10 of 10	ENSP00000397691.3
	TMPRSS6	ENST00000676104.1	MANE Select	c.1196+66T>G		intron	N/A	ENSP00000501573.1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1196+66T>G		intron	N/A	ENSP00000384964.1

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148186 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000248

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

GnomAD4 exome AF: 8.45e-7 AC: 1 AN: 1183348 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 594934

African (AFR) AF: 0.00 AC: 0 AN: 27350

American (AMR) AF: 0.00 AC: 0 AN: 36200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22722

East Asian (EAS) AF: 0.00 AC: 0 AN: 33094

South Asian (SAS) AF: 0.00 AC: 0 AN: 76198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5172

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 883766

Other (OTH) AF: 0.00 AC: 0 AN: 49916

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148186 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 72140

African (AFR) AF: 0.0000248 AC: 1 AN: 40340

American (AMR) AF: 0.00 AC: 0 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4652

South Asian (SAS) AF: 0.00 AC: 0 AN: 4466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67056

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 2694

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.24
DANN	Benign	0.46
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.86	T
PhyloP100		-0.81
PROVEAN	Benign	0.0	N
REVEL	Benign	0.067
Sift	Benign	0.087	T
Sift4G	Benign	0.14	T
Vest4		0.27
MutPred		0.44		Gain of solvent accessibility (P = 6e-04)
MVP		0.73
ClinPred		0.040	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs2543519; hg19: chr22-37480269;