NM_001374504.1:c.1556-198G>A

Variant names:

• chr22-37071230-C-T
• rs5756504
• NM_001374504.1:c.1556-198G>A

Variant summary

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

The NM_001374504.1(TMPRSS6):​c.1556-198G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 149,462 control chromosomes in the GnomAD database, including 14,951 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 0.43 (14951 hom., cov: 25)
• Consequence: TMPRSS6 NM_001374504.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.66
• Publications: 30 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.615 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	NM_001374504.1	MANE Select	c.1556-198G>A		intron	N/A	NP_001361433.1
	TMPRSS6	NM_001289000.2		c.1556-198G>A		intron	N/A	NP_001275929.1
	TMPRSS6	NM_001289001.2		c.1556-198G>A		intron	N/A	NP_001275930.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.1556-198G>A		intron	N/A	ENSP00000501573.1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1556-198G>A		intron	N/A	ENSP00000384964.1
	TMPRSS6	ENST00000346753.9	TSL:1	c.1556-198G>A		intron	N/A	ENSP00000334962.6

Frequencies

GnomAD3 genomes AF: 0.427 AC: 63831 AN: 149344 Hom.: 14922 Cov.: 25

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.395

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

GnomAD4 genome AF: 0.428 AC: 63904 AN: 149462 Hom.: 14951 Cov.: 25 AF XY: 0.422 AC XY: 30765 AN XY: 72880

African (AFR) AF: 0.621 AC: 24980 AN: 40216

American (AMR) AF: 0.288 AC: 4364 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1348 AN: 3456

East Asian (EAS) AF: 0.447 AC: 2224 AN: 4974

South Asian (SAS) AF: 0.258 AC: 1212 AN: 4706

European-Finnish (FIN) AF: 0.406 AC: 4142 AN: 10192

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24372 AN: 67506

Other (OTH) AF: 0.391 AC: 813 AN: 2078

Alfa AF: 0.381 Hom.: 36785

Bravo AF: 0.436

Asia WGS AF: 0.313 AC: 1085 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.41
DANN	Benign	0.42
PhyloP100		-2.7
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: rs5756504; hg19: chr22-37467270;