22-37066082-A-C

Variant names:

• chr22-37066082-A-C
• rs2146016503
• NM_001374504.1:c.2407T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001374504.1(TMPRSS6):​c.2407T>G​(p.Ter803Glyext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPRSS6 NM_001374504.1 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.32
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001374504.1 Downstream stopcodon found after 32 codons.
• PP5: Variant 22-37066082-A-C is Pathogenic according to our data. Variant chr22-37066082-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1675886.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374504.1. 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.2407T>G	p.Ter803Glyext*?	stop_lost	Exon 18 of 18	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.2473T>G	p.Ter825Glyext*?	stop_lost	Exon 19 of 19	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.2407T>G	p.Ter803Glyext*?	stop_lost	Exon 18 of 18	NP_001275930.1	Q8IU80-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.2407T>G	p.Ter803Glyext*?	stop_lost	Exon 18 of 18	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.2473T>G	p.Ter825Glyext*?	stop_lost	Exon 19 of 19	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.2407T>G	p.Ter803Glyext*?	stop_lost	Exon 18 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.5
DANN	Benign	0.75
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		3.3
Vest4		0.17
GERP RS		4.6
Mutation Taster		=11/189	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2146016503; hg19: chr22-37462122;