22-37066896-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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374504.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	NM_001374504.1	MANE Select	c.2180T>C	p.Val727Ala	missense	Exon 17 of 18	NP_001361433.1
	TMPRSS6	NM_001289000.2		c.2246T>C	p.Val749Ala	missense	Exon 18 of 19	NP_001275929.1
	TMPRSS6	NM_001289001.2		c.2180T>C	p.Val727Ala	missense	Exon 17 of 18	NP_001275930.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.2180T>C	p.Val727Ala	missense	Exon 17 of 18	ENSP00000501573.1
	TMPRSS6	ENST00000406856.7	TSL:1	c.2246T>C	p.Val749Ala	missense	Exon 18 of 19	ENSP00000384964.1
	TMPRSS6	ENST00000346753.9	TSL:1	c.2180T>C	p.Val727Ala	missense	Exon 17 of 18	ENSP00000334962.6

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Iron-refractory iron deficiency anemia (1)
-	-	1	Microcytic anemia (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000039	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.0	N
PhyloP100		4.8
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.26	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.19
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;