rs733655

Variant names:

• chr22-37099011-T-C
• rs733655
• NM_001374504.1:c.203-462A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001374504.1(TMPRSS6):​c.203-462A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,080 control chromosomes in the GnomAD database, including 5,972 homozygotes. 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: 𝑓 0.27 (5972 hom., cov: 33)
• Consequence: TMPRSS6 NM_001374504.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.30
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.203-462A>G		intron_variant	Intron 2 of 17	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.203-462A>G		intron_variant	Intron 2 of 17		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40925 AN: 151962 Hom.: 5967 Cov.: 33

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.272

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.269 AC: 40969 AN: 152080 Hom.: 5972 Cov.: 33 AF XY: 0.265 AC XY: 19731 AN XY: 74346

African (AFR) AF: 0.379 AC: 15735 AN: 41472

American (AMR) AF: 0.182 AC: 2783 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 886 AN: 3472

East Asian (EAS) AF: 0.200 AC: 1033 AN: 5172

South Asian (SAS) AF: 0.129 AC: 621 AN: 4826

European-Finnish (FIN) AF: 0.270 AC: 2858 AN: 10572

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16310 AN: 67956

Other (OTH) AF: 0.269 AC: 568 AN: 2112

Alfa AF: 0.251 Hom.: 802

Bravo AF: 0.270

Asia WGS AF: 0.173 AC: 605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.17
DANN	Benign	0.62
PhyloP100		-3.3
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: rs733655; hg19: chr22-37495051;