rs11704654

Variant names:

• chr22-37103346-C-T
• rs11704654
• NM_001374504.1:c.72G>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.72G>A​(p.Pro24Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,614,092 control chromosomes in the GnomAD database, including 29,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2276 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27648 hom.)
• Consequence: TMPRSS6 NM_001374504.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.88
• Publications: 20 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=-0.68).
• BP6: Variant 22-37103346-C-T is Benign according to our data. Variant chr22-37103346-C-T is described in ClinVar as Benign. ClinVar VariationId is 262729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.88 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.193 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.72G>A	p.Pro24Pro	synonymous	Exon 2 of 18	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.72G>A	p.Pro24Pro	synonymous	Exon 2 of 19	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.72G>A	p.Pro24Pro	synonymous	Exon 2 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.72G>A	p.Pro24Pro	synonymous	Exon 2 of 18	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.72G>A	p.Pro24Pro	synonymous	Exon 2 of 19	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.72G>A	p.Pro24Pro	synonymous	Exon 2 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25627 AN: 152124 Hom.: 2273 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.162 AC: 40709 AN: 251418 AF XY: 0.163

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0964

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.191 AC: 279147 AN: 1461850 Hom.: 27648 Cov.: 37 AF XY: 0.190 AC XY: 138066 AN XY: 727226

African (AFR) AF: 0.149 AC: 4983 AN: 33478

American (AMR) AF: 0.101 AC: 4522 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 5152 AN: 26134

East Asian (EAS) AF: 0.155 AC: 6148 AN: 39700

South Asian (SAS) AF: 0.125 AC: 10803 AN: 86258

European-Finnish (FIN) AF: 0.158 AC: 8415 AN: 53406

Middle Eastern (MID) AF: 0.144 AC: 829 AN: 5768

European-Non Finnish (NFE) AF: 0.204 AC: 227282 AN: 1111990

Other (OTH) AF: 0.182 AC: 11013 AN: 60392

GnomAD4 genome AF: 0.169 AC: 25656 AN: 152242 Hom.: 2276 Cov.: 32 AF XY: 0.167 AC XY: 12408 AN XY: 74448

African (AFR) AF: 0.147 AC: 6094 AN: 41544

American (AMR) AF: 0.130 AC: 1986 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 680 AN: 3472

East Asian (EAS) AF: 0.142 AC: 736 AN: 5178

South Asian (SAS) AF: 0.133 AC: 643 AN: 4822

European-Finnish (FIN) AF: 0.154 AC: 1635 AN: 10616

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13288 AN: 67994

Other (OTH) AF: 0.172 AC: 364 AN: 2114

Alfa AF: 0.192 Hom.: 3518

Bravo AF: 0.167

Asia WGS AF: 0.138 AC: 482 AN: 3478

EpiCase AF: 0.192

EpiControl AF: 0.197

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Iron-refractory iron deficiency anemia (1)
-	-	1	Microcytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.30
DANN	Benign	0.80
PhyloP100		-2.9
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs11704654; hg19: chr22-37499386; COSMIC: COSV108186173;