22-37082214-A-G

Variant names:

• chr22-37082214-A-G
• rs1005478
• NM_001374504.1:c.1196+2081T>C

Variant summary

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

The NM_001374504.1(TMPRSS6):​c.1196+2081T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 152,094 control chromosomes in the GnomAD database, including 33,315 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 0.64 (33315 hom., cov: 32)
• Consequence: TMPRSS6 NM_001374504.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.669
• Publications: 10 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

ENSG00000231467 (HGNC:40775):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.863 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.1196+2081T>C		intron	N/A	NP_001361433.1
	TMPRSS6	NM_001289000.2		c.1196+2081T>C		intron	N/A	NP_001275929.1
	TMPRSS6	NM_001289001.2		c.1196+2081T>C		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.1196+2081T>C		intron	N/A	ENSP00000501573.1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1196+2081T>C		intron	N/A	ENSP00000384964.1
	TMPRSS6	ENST00000346753.9	TSL:1	c.1196+2081T>C		intron	N/A	ENSP00000334962.6

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97811 AN: 151976 Hom.: 33262 Cov.: 32

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.644 AC: 97911 AN: 152094 Hom.: 33315 Cov.: 32 AF XY: 0.641 AC XY: 47677 AN XY: 74336

African (AFR) AF: 0.871 AC: 36135 AN: 41496

American (AMR) AF: 0.442 AC: 6765 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1833 AN: 3468

East Asian (EAS) AF: 0.493 AC: 2538 AN: 5150

South Asian (SAS) AF: 0.468 AC: 2258 AN: 4824

European-Finnish (FIN) AF: 0.677 AC: 7155 AN: 10576

Middle Eastern (MID) AF: 0.531 AC: 155 AN: 292

European-Non Finnish (NFE) AF: 0.580 AC: 39433 AN: 67976

Other (OTH) AF: 0.594 AC: 1255 AN: 2112

Alfa AF: 0.577 Hom.: 25555

Bravo AF: 0.639

Asia WGS AF: 0.459 AC: 1597 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.33
DANN	Benign	0.37
PhyloP100		-0.67
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: rs1005478; hg19: chr22-37478254; COSMIC: COSV60974848; COSMIC: COSV60974848;