22-37103525-G-C

Variant names:

• chr22-37103525-G-C
• rs115270691
• ENST00000346753.9:c.-13C>G

Variant summary

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

The NM_153609.4(TMPRSS6):​c.-13C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMPRSS6 NM_153609.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0884361).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153609.4. 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.-1-107C>G		intron	N/A	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_153609.4		c.-13C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_705837.2	Q8IU80-1
	TMPRSS6	NM_153609.4		c.-13C>G		5_prime_UTR	Exon 1 of 18	NP_705837.2	Q8IU80-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000346753.9	TSL:1	c.-13C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000334962.6	Q8IU80-1
	TMPRSS6	ENST00000442782.7	TSL:1	c.-13C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000397691.3	X6REP5
	TMPRSS6	ENST00000346753.9	TSL:1	c.-13C>G		5_prime_UTR	Exon 1 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 47

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	3.6
DANN	Benign	0.92
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.042
MutPred		0.31		Loss of sheet (P = 0.0357)
MVP		0.66
MPC		0.18
ClinPred		0.070	T
GERP RS		0.40
PromoterAI		-0.038	Neutral
Varity_R		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs115270691; hg19: chr22-37499565;