rs2543519

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000442782.7(TMPRSS6):​c.1262T>C​(p.Ile421Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,329,838 control chromosomes in the GnomAD database, including 39,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I421K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (5438 hom., cov: 29)
  • Exomes 𝑓: 0.24 (34445 hom.)
• Consequence: TMPRSS6 ENST00000442782.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025805533).
• BP6: Variant 22-37084229-A-G is Benign according to our data. Variant chr22-37084229-A-G is described in ClinVar as Benign. ClinVar VariationId is 1261467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	NM_001374504.1	MANE Select	c.1196+66T>C		intron	N/A	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.1196+66T>C		intron	N/A	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.1196+66T>C		intron	N/A	NP_001275930.1	Q8IU80-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000442782.7	TSL:1	c.1262T>C	p.Ile421Thr	missense	Exon 10 of 10	ENSP00000397691.3	X6REP5
	TMPRSS6	ENST00000676104.1	MANE Select	c.1196+66T>C		intron	N/A	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1196+66T>C		intron	N/A	ENSP00000384964.1	Q8IU80-5

Frequencies

GnomAD3 genomes AF: 0.264 AC: 39069 AN: 148056 Hom.: 5429 Cov.: 29

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.0980

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.259

GnomAD2 exomes AF: 0.223 AC: 40819 AN: 182858 AF XY: 0.222

Gnomad AFR exome AF: 0.367

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.190

Gnomad FIN exome AF: 0.263

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.241 AC: 284487 AN: 1181636 Hom.: 34445 Cov.: 17 AF XY: 0.239 AC XY: 142042 AN XY: 594082

African (AFR) AF: 0.375 AC: 10228 AN: 27310

American (AMR) AF: 0.136 AC: 4907 AN: 36190

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 5900 AN: 22706

East Asian (EAS) AF: 0.172 AC: 5702 AN: 33082

South Asian (SAS) AF: 0.204 AC: 15548 AN: 76154

European-Finnish (FIN) AF: 0.270 AC: 13193 AN: 48904

Middle Eastern (MID) AF: 0.183 AC: 948 AN: 5170

European-Non Finnish (NFE) AF: 0.245 AC: 215907 AN: 882270

Other (OTH) AF: 0.244 AC: 12154 AN: 49850

GnomAD4 genome AF: 0.264 AC: 39119 AN: 148202 Hom.: 5438 Cov.: 29 AF XY: 0.263 AC XY: 18959 AN XY: 72204

African (AFR) AF: 0.353 AC: 14275 AN: 40404

American (AMR) AF: 0.181 AC: 2708 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 848 AN: 3448

East Asian (EAS) AF: 0.191 AC: 884 AN: 4638

South Asian (SAS) AF: 0.220 AC: 980 AN: 4458

European-Finnish (FIN) AF: 0.276 AC: 2770 AN: 10028

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.238 AC: 15963 AN: 67026

Other (OTH) AF: 0.256 AC: 536 AN: 2092

Alfa AF: 0.230 Hom.: 2694

Bravo AF: 0.259

TwinsUK AF: 0.229 AC: 849

ALSPAC AF: 0.244 AC: 940

ExAC AF: 0.197 AC: 23221

Asia WGS AF: 0.211 AC: 736 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.28
DANN	Benign	0.48
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0038	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.81
PROVEAN	Benign	0.93	N
REVEL	Benign	0.053
Sift	Benign	0.16	T
Sift4G	Benign	0.21	T
Vest4		0.028
ClinPred		0.00040	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV60975105; COSMIC: COSV60975105;