chr22-37066896-A-G

Variant names:

• chr22-37066896-A-G
• rs855791
• NM_001374504.1:c.2180T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374504.1(TMPRSS6):​c.2180T>C​(p.Val727Ala) variant causes a missense change. The variant allele was found at a frequency of 0.57 in 1,613,526 control chromosomes in the GnomAD database, including 267,184 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32125 hom., cov: 33)
  • Exomes 𝑓: 0.56 (235059 hom.)
• Consequence: TMPRSS6 NM_001374504.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.84
• Publications: 299 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.892132E-6).
• BP6: Variant 22-37066896-A-G is Benign according to our data. Variant chr22-37066896-A-G is described in ClinVar as Benign. ClinVar VariationId is 262725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.2180T>C	p.Val727Ala	missense_variant	Exon 17 of 18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.2180T>C	p.Val727Ala	missense_variant	Exon 17 of 18		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96440 AN: 151832 Hom.: 32071 Cov.: 33

Gnomad AFR AF: 0.846

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.592

GnomAD2 exomes AF: 0.566 AC: 141752 AN: 250414 AF XY: 0.558

Gnomad AFR exome AF: 0.859

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.544

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.658

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.558

GnomAD4 exome AF: 0.563 AC: 823260 AN: 1461576 Hom.: 235059 Cov.: 62 AF XY: 0.560 AC XY: 407285 AN XY: 727070

African (AFR) AF: 0.865 AC: 28947 AN: 33480

American (AMR) AF: 0.520 AC: 23230 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 14119 AN: 26134

East Asian (EAS) AF: 0.444 AC: 17610 AN: 39686

South Asian (SAS) AF: 0.480 AC: 41380 AN: 86252

European-Finnish (FIN) AF: 0.655 AC: 34937 AN: 53344

Middle Eastern (MID) AF: 0.594 AC: 3424 AN: 5768

European-Non Finnish (NFE) AF: 0.562 AC: 625110 AN: 1111836

Other (OTH) AF: 0.571 AC: 34503 AN: 60382

GnomAD4 genome AF: 0.635 AC: 96540 AN: 151950 Hom.: 32125 Cov.: 33 AF XY: 0.631 AC XY: 46824 AN XY: 74240

African (AFR) AF: 0.846 AC: 35091 AN: 41472

American (AMR) AF: 0.516 AC: 7890 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1949 AN: 3460

East Asian (EAS) AF: 0.446 AC: 2303 AN: 5164

South Asian (SAS) AF: 0.461 AC: 2218 AN: 4814

European-Finnish (FIN) AF: 0.652 AC: 6878 AN: 10544

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.564 AC: 38273 AN: 67902

Other (OTH) AF: 0.586 AC: 1237 AN: 2110

Alfa AF: 0.579 Hom.: 111646

Bravo AF: 0.639

TwinsUK AF: 0.553 AC: 2051

ALSPAC AF: 0.540 AC: 2081

ESP6500AA AF: 0.842 AC: 3708

ESP6500EA AF: 0.565 AC: 4858

ExAC AF: 0.572 AC: 69384

EpiCase AF: 0.571

EpiControl AF: 0.557

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25312922, 22265928, 25601433, 23293981, 20738301, 24661031, 21873547, 23433094, 22885719, 21785125, 19820698, 23222517, 23144979, 19820699, 27346686, 28447549, 30963028, 31640930, 25557470)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Microcytic anemia Benign:1

Mar 06, 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.

Iron-refractory iron deficiency anemia Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.017	T;T;T;.
MetaRNN	Benign	0.0000039	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.0	N;.;.;.
PhyloP100		4.8
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.26	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.73	T;T;T;T
Vest4		0.038
ClinPred		0.0046	T
GERP RS		4.7
Varity_R		0.068
gMVP		0.28
Mutation Taster		=99/1	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: rs855791; hg19: chr22-37462936; COSMIC: COSV60975328; COSMIC: COSV60975328;