rs11704654

chr22-37103346-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001374504.1(TMPRSS6):c.72G>A(p.Pro24=) 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:7
• Conservation: PhyloP100: -2.88

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 262729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37103346-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS6	NM_001374504.1	c.72G>A	p.Pro24=	synonymous_variant	2/18	ENST00000676104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.72G>A	p.Pro24=	synonymous_variant	2/18		NM_001374504.1	P1

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

GnomAD3 exomes AF: 0.162 AC: 40709 AN: 251418 Hom.: 3593 AF XY: 0.163 AC XY: 22211 AN XY: 135898

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 SAS exome AF: 0.122

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

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.204

Gnomad4 OTH exome AF: 0.182

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

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.172

Alfa AF: 0.193 Hom.: 3196

Bravo AF: 0.167

Asia WGS AF: 0.138 AC: 482 AN: 3478

EpiCase AF: 0.192

EpiControl AF: 0.197

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Microcytic anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Iron-refractory iron deficiency anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.30
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs11704654; hg19: chr22-37499386;