rs4820268

Positions:

• chr22-37073551-G-A
• chr22-37073551-G-C
• chr22-37073551-G-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.1536C>T​(p.Asp512=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,611,200 control chromosomes in the GnomAD database, including 237,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26621 hom., cov: 32)
  • Exomes 𝑓: 0.53 (210838 hom.)
• Consequence: TMPRSS6 NM_001374504.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.71

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 22-37073551-G-A is Benign according to our data. Variant chr22-37073551-G-A is described in ClinVar as [Benign]. Clinvar id is 262722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37073551-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.1536C>T	p.Asp512=	synonymous_variant	13/18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.1536C>T	p.Asp512=	synonymous_variant	13/18		NM_001374504.1	ENSP00000501573	P1

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88477 AN: 151916 Hom.: 26588 Cov.: 32

Gnomad AFR AF: 0.731

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.555

GnomAD3 exomes AF: 0.535 AC: 134439 AN: 251322 Hom.: 36568 AF XY: 0.528 AC XY: 71757 AN XY: 135838

Gnomad AFR exome AF: 0.736

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.538

Gnomad EAS exome AF: 0.473

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.535 AC: 780612 AN: 1459166 Hom.: 210838 Cov.: 35 AF XY: 0.533 AC XY: 386683 AN XY: 726054

Gnomad4 AFR exome AF: 0.736

Gnomad4 AMR exome AF: 0.504

Gnomad4 ASJ exome AF: 0.533

Gnomad4 EAS exome AF: 0.460

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.537

Gnomad4 OTH exome AF: 0.537

GnomAD4 genome AF: 0.582 AC: 88552 AN: 152034 Hom.: 26621 Cov.: 32 AF XY: 0.575 AC XY: 42754 AN XY: 74318

Gnomad4 AFR AF: 0.731

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.553

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.434

Gnomad4 FIN AF: 0.564

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.548

Alfa AF: 0.541 Hom.: 38029

Bravo AF: 0.588

Asia WGS AF: 0.413 AC: 1435 AN: 3478

EpiCase AF: 0.543

EpiControl AF: 0.536

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Iron-refractory iron deficiency anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 20, 2021	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.020
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4820268; hg19: chr22-37469591; COSMIC: COSV60976234;