22-37084757-C-T

Variant names:

• chr22-37084757-C-T
• rs2111833
• NM_001374504.1:c.1056G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001374504.1(TMPRSS6):​c.1056G>A​(p.Ser352Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,564,542 control chromosomes in the GnomAD database, including 90,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9173 hom., cov: 32)
  • Exomes 𝑓: 0.34 (81511 hom.)
• Consequence: TMPRSS6 NM_001374504.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.67
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 22-37084757-C-T is Benign according to our data. Variant chr22-37084757-C-T is described in ClinVar as Benign. ClinVar VariationId is 262719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 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.1056G>A	p.Ser352Ser	synonymous	Exon 9 of 18	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.1056G>A	p.Ser352Ser	synonymous	Exon 9 of 19	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.1056G>A	p.Ser352Ser	synonymous	Exon 9 of 18	NP_001275930.1	Q8IU80-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.1056G>A	p.Ser352Ser	synonymous	Exon 9 of 18	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1056G>A	p.Ser352Ser	synonymous	Exon 9 of 19	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.1056G>A	p.Ser352Ser	synonymous	Exon 9 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52029 AN: 151832 Hom.: 9174 Cov.: 32

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.306

GnomAD2 exomes AF: 0.312 AC: 55328 AN: 177408 AF XY: 0.311

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.320

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.337 AC: 475763 AN: 1412592 Hom.: 81511 Cov.: 44 AF XY: 0.335 AC XY: 233597 AN XY: 697920

African (AFR) AF: 0.384 AC: 12497 AN: 32550

American (AMR) AF: 0.220 AC: 8191 AN: 37174

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6740 AN: 25276

East Asian (EAS) AF: 0.319 AC: 11925 AN: 37378

South Asian (SAS) AF: 0.272 AC: 21841 AN: 80230

European-Finnish (FIN) AF: 0.408 AC: 20428 AN: 50106

Middle Eastern (MID) AF: 0.308 AC: 1569 AN: 5086

European-Non Finnish (NFE) AF: 0.344 AC: 373366 AN: 1086204

Other (OTH) AF: 0.328 AC: 19206 AN: 58588

GnomAD4 genome AF: 0.343 AC: 52046 AN: 151950 Hom.: 9173 Cov.: 32 AF XY: 0.344 AC XY: 25561 AN XY: 74240

African (AFR) AF: 0.382 AC: 15821 AN: 41424

American (AMR) AF: 0.246 AC: 3765 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 945 AN: 3472

East Asian (EAS) AF: 0.328 AC: 1693 AN: 5162

South Asian (SAS) AF: 0.261 AC: 1260 AN: 4826

European-Finnish (FIN) AF: 0.410 AC: 4328 AN: 10556

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23224 AN: 67912

Other (OTH) AF: 0.302 AC: 638 AN: 2112

Alfa AF: 0.338 Hom.: 35463

Bravo AF: 0.334

Asia WGS AF: 0.236 AC: 818 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Microcytic anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.48
DANN	Benign	0.85
PhyloP100		-2.7
PromoterAI		-0.013	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2111833; hg19: chr22-37480797; COSMIC: COSV60977518; COSMIC: COSV60977518;