22-37069081-C-T

Variant names:

• chr22-37069081-C-T
• rs115310908
• NM_001374504.1:c.2105G>A

Variant summary

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

The NM_001374504.1(TMPRSS6):​c.2105G>A​(p.Arg702His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,390,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R702L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMPRSS6 NM_001374504.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.667
• Publications: 1 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	NM_001374504.1	MANE Select	c.2105G>A	p.Arg702His	missense	Exon 16 of 18	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.2105G>A	p.Arg702His	missense	Exon 16 of 19	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.2105G>A	p.Arg702His	missense	Exon 16 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.2105G>A	p.Arg702His	missense	Exon 16 of 18	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.2105G>A	p.Arg702His	missense	Exon 16 of 19	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.2105G>A	p.Arg702His	missense	Exon 16 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000708 AC: 1 AN: 141312 AF XY: 0.0000130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1390832 Hom.: 0 Cov.: 36 AF XY: 0.00000291 AC XY: 2 AN XY: 686868

African (AFR) AF: 0.00 AC: 0 AN: 31708

American (AMR) AF: 0.00 AC: 0 AN: 36678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35956

South Asian (SAS) AF: 0.00 AC: 0 AN: 79614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4774

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081414

Other (OTH) AF: 0.0000173 AC: 1 AN: 57952

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.67
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.023	D
Sift4G	Benign	0.31	T
Polyphen		0.99	D
Vest4		0.25
MutPred		0.57		Gain of disorder (P = 0.1083)
MVP		0.94
MPC		0.21
ClinPred		0.78	D
GERP RS		3.6
Varity_R		0.14
gMVP		0.49
Mutation Taster		=94/6	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: rs115310908; hg19: chr22-37465121;