rs2235324

Variant names:

• chr22-37089684-T-C
• rs2235324
• NM_001374504.1:c.730A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-37089684-T-C
• chr22-37089684-T-G

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.730A>G​(p.Lys244Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,611,216 control chromosomes in the GnomAD database, including 123,383 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (12213 hom., cov: 33)
  • Exomes 𝑓: 0.39 (111170 hom.)
• Consequence: TMPRSS6 NM_001374504.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.74
• Publications: 51 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=4.389584E-4).
• BP6: Variant 22-37089684-T-C is Benign according to our data. Variant chr22-37089684-T-C is described in ClinVar as Benign. ClinVar VariationId is 262728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.730A>G	p.Lys244Glu	missense_variant	Exon 7 of 18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.730A>G	p.Lys244Glu	missense_variant	Exon 7 of 18		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60430 AN: 151986 Hom.: 12211 Cov.: 33

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.379

GnomAD2 exomes AF: 0.382 AC: 93182 AN: 244230 AF XY: 0.382

Gnomad AFR exome AF: 0.425

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.403

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.386

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.389 AC: 567579 AN: 1459110 Hom.: 111170 Cov.: 65 AF XY: 0.389 AC XY: 281950 AN XY: 725612

African (AFR) AF: 0.435 AC: 14549 AN: 33446

American (AMR) AF: 0.326 AC: 14455 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 8549 AN: 26064

East Asian (EAS) AF: 0.443 AC: 17569 AN: 39622

South Asian (SAS) AF: 0.385 AC: 33015 AN: 85792

European-Finnish (FIN) AF: 0.426 AC: 22534 AN: 52900

Middle Eastern (MID) AF: 0.386 AC: 2201 AN: 5708

European-Non Finnish (NFE) AF: 0.388 AC: 431323 AN: 1110904

Other (OTH) AF: 0.388 AC: 23384 AN: 60266

GnomAD4 genome AF: 0.397 AC: 60454 AN: 152106 Hom.: 12213 Cov.: 33 AF XY: 0.401 AC XY: 29783 AN XY: 74364

African (AFR) AF: 0.432 AC: 17932 AN: 41488

American (AMR) AF: 0.363 AC: 5554 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1140 AN: 3464

East Asian (EAS) AF: 0.414 AC: 2141 AN: 5170

South Asian (SAS) AF: 0.371 AC: 1786 AN: 4820

European-Finnish (FIN) AF: 0.428 AC: 4531 AN: 10580

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.384 AC: 26090 AN: 67986

Other (OTH) AF: 0.374 AC: 791 AN: 2116

Alfa AF: 0.385 Hom.: 39624

Bravo AF: 0.395

TwinsUK AF: 0.396 AC: 1468

ALSPAC AF: 0.380 AC: 1466

ESP6500AA AF: 0.425 AC: 1871

ESP6500EA AF: 0.381 AC: 3280

ExAC AF: 0.383 AC: 46453

Asia WGS AF: 0.349 AC: 1213 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	0.054
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.011
DANN	Benign	0.21
DEOGEN2	Benign	0.055	T;.;.;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.077	T;T;T;.;T
MetaRNN	Benign	0.00044	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N;.;.;.;.
PhyloP100		-1.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.14	N;N;N;N;N
REVEL	Benign	0.023
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;.;B;.
Vest4		0.050
MPC		0.22
ClinPred		0.015	T
GERP RS		-9.2
Varity_R		0.037
gMVP		0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2235324; hg19: chr22-37485724; COSMIC: COSV60974516; COSMIC: COSV60974516;