dbSNP rs4820268: TMPRSS6:p.Asp512Asp (chr22-37073551-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001374504.1(TMPRSS6):c.1536C>T(p.Asp512Asp) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.71

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1 link	c.1536C>T	p.Asp512Asp	synonymous_variant	Exon 13 of 18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1 link	c.1536C>T	p.Asp512Asp	synonymous_variant	Exon 13 of 18		NM_001374504.1	ENSP00000501573.1		Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.582

AC:

88477

AN:

151916

Hom.:

26588

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.533

AC XY:

386683

AN XY:

726054

show subpopulations

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.:

AF XY:

0.575

AC XY:

42754

AN XY:

74318

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Iron-refractory iron deficiency anemia

Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcytic anemia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over