22-37071314-G-C

Variant names:

• chr22-37071314-G-C
• rs5756505
• NM_001374504.1:c.1556-282C>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.1556-282C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 151,712 control chromosomes in the GnomAD database, including 19,937 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 0.48 (19937 hom., cov: 30)
• Consequence: TMPRSS6 NM_001374504.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.735
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

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.1556-282C>G		intron	N/A	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.1556-282C>G		intron	N/A	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.1556-282C>G		intron	N/A	NP_001275930.1	Q8IU80-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.1556-282C>G		intron	N/A	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1556-282C>G		intron	N/A	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.1556-282C>G		intron	N/A	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73282 AN: 151594 Hom.: 19902 Cov.: 30

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.448

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

GnomAD4 genome AF: 0.484 AC: 73361 AN: 151712 Hom.: 19937 Cov.: 30 AF XY: 0.478 AC XY: 35410 AN XY: 74132

African (AFR) AF: 0.745 AC: 30796 AN: 41326

American (AMR) AF: 0.322 AC: 4912 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1431 AN: 3468

East Asian (EAS) AF: 0.455 AC: 2333 AN: 5126

South Asian (SAS) AF: 0.265 AC: 1273 AN: 4812

European-Finnish (FIN) AF: 0.450 AC: 4729 AN: 10504

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.390 AC: 26476 AN: 67898

Other (OTH) AF: 0.444 AC: 935 AN: 2108

Alfa AF: 0.424 Hom.: 1795

Bravo AF: 0.490

Asia WGS AF: 0.328 AC: 1138 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.77
DANN	Benign	0.40
PhyloP100		-0.73
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: rs5756505; hg19: chr22-37467354;