22-37091770-A-G

Variant names:

• chr22-37091770-A-G
• rs1421312
• NM_001374504.1:c.632-1988T>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.632-1988T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 152,080 control chromosomes in the GnomAD database, including 16,093 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 0.45 (16093 hom., cov: 32)
• Consequence: TMPRSS6 NM_001374504.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• Publications: 14 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.632-1988T>C		intron_variant	Intron 6 of 17	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.632-1988T>C		intron_variant	Intron 6 of 17		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68328 AN: 151962 Hom.: 16077 Cov.: 32

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.450 AC: 68387 AN: 152080 Hom.: 16093 Cov.: 32 AF XY: 0.452 AC XY: 33627 AN XY: 74330

African (AFR) AF: 0.593 AC: 24601 AN: 41476

American (AMR) AF: 0.382 AC: 5844 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1170 AN: 3470

East Asian (EAS) AF: 0.416 AC: 2148 AN: 5168

South Asian (SAS) AF: 0.470 AC: 2269 AN: 4828

European-Finnish (FIN) AF: 0.431 AC: 4562 AN: 10574

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26422 AN: 67964

Other (OTH) AF: 0.412 AC: 870 AN: 2110

Alfa AF: 0.401 Hom.: 21217

Bravo AF: 0.450

Asia WGS AF: 0.416 AC: 1443 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.9
DANN	Benign	0.58
PhyloP100		0.087
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: rs1421312; hg19: chr22-37487810;