chr22-37066896-A-C

Variant names:

• chr22-37066896-A-C
• rs855791
• NM_001374504.1:c.2180T>G

Variant summary

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

The NM_001374504.1(TMPRSS6):​c.2180T>G​(p.Val727Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V727A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPRSS6 NM_001374504.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.84
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	NM_001374504.1	MANE Select	c.2180T>G	p.Val727Gly	missense	Exon 17 of 18	NP_001361433.1
	TMPRSS6	NM_001289000.2		c.2246T>G	p.Val749Gly	missense	Exon 18 of 19	NP_001275929.1
	TMPRSS6	NM_001289001.2		c.2180T>G	p.Val727Gly	missense	Exon 17 of 18	NP_001275930.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.2180T>G	p.Val727Gly	missense	Exon 17 of 18	ENSP00000501573.1
	TMPRSS6	ENST00000406856.7	TSL:1	c.2246T>G	p.Val749Gly	missense	Exon 18 of 19	ENSP00000384964.1
	TMPRSS6	ENST00000346753.9	TSL:1	c.2180T>G	p.Val727Gly	missense	Exon 17 of 18	ENSP00000334962.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.14	T
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.055	N
PhyloP100		4.8
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.37
Sift	Benign	0.16	T
Sift4G	Uncertain	0.027	D
Polyphen		0.0	B
Vest4		0.16
MutPred		0.53		Loss of stability (P = 0.0032)
MVP		0.76
MPC		0.21
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.27
gMVP		0.39
Mutation Taster		=98/2	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: rs855791; hg19: chr22-37462936;