rs117576908

chr22-37075168-G-Achr22-37075168-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374504.1(TMPRSS6):c.1309C>T(p.Arg437Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,614,034 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R437G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0080 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (136 hom.)
• Consequence: TMPRSS6 NM_001374504.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.32

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005034983).
• BP6: Variant 22-37075168-G-A is Benign according to our data. Variant chr22-37075168-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37075168-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00799 (1217/152320) while in subpopulation NFE AF= 0.00681 (463/68020). AF 95% confidence interval is 0.00629. There are 25 homozygotes in gnomad4. There are 769 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS6	NM_001374504.1	c.1309C>T	p.Arg437Trp	missense_variant	11/18	ENST00000676104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.1309C>T	p.Arg437Trp	missense_variant	11/18		NM_001374504.1	P1

Frequencies

GnomAD3 genomes AF: 0.00800 AC: 1217 AN: 152202 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00681

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00950 AC: 2387 AN: 251220 Hom.: 42 AF XY: 0.00961 AC XY: 1305 AN XY: 135830

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.0569

Gnomad NFE exome AF: 0.00769

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00768 AC: 11228 AN: 1461714 Hom.: 136 Cov.: 33 AF XY: 0.00753 AC XY: 5479 AN XY: 727180

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00457

Gnomad4 FIN exome AF: 0.0552

Gnomad4 NFE exome AF: 0.00661

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.00799 AC: 1217 AN: 152320 Hom.: 25 Cov.: 33 AF XY: 0.0103 AC XY: 769 AN XY: 74482

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0596

Gnomad4 NFE AF: 0.00681

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00571 Hom.: 2

Bravo AF: 0.00382

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00836 AC: 1015

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TMPRSS6: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 25, 2015	- -

Microcytic anemia Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;.
MetaRNN	Benign	0.0050	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;.;.;.
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.060	T;T;T;T
Sift4G	Uncertain	0.041	D;D;D;D
Polyphen		0.88	P;P;.;P
Vest4		0.51
MVP		0.67
MPC		0.30
ClinPred		0.021	T
GERP RS		5.3
Varity_R		0.17
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs117576908; hg19: chr22-37471208; COSMIC: COSV99061788; COSMIC: COSV99061788;