NM_001374504.1:c.2356G>A

Variant names:

• chr22-37066133-C-T
• rs139105452
• NM_001374504.1:c.2356G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001374504.1(TMPRSS6):​c.2356G>A​(p.Val786Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0101 in 1,613,366 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0083 (4 hom., cov: 33)
  • Exomes 𝑓: 0.010 (96 hom.)
• Consequence: TMPRSS6 NM_001374504.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 6.05
• Publications: 22 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017411858).
• BP6: Variant 22-37066133-C-T is Benign according to our data. Variant chr22-37066133-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262727.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00829 (1262/152222) while in subpopulation NFE AF = 0.01 (680/67978). AF 95% confidence interval is 0.00938. There are 4 homozygotes in GnomAd4. There are 627 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.2356G>A	p.Val786Ile	missense	Exon 18 of 18	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.2422G>A	p.Val808Ile	missense	Exon 19 of 19	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.2356G>A	p.Val786Ile	missense	Exon 18 of 18	NP_001275930.1	Q8IU80-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.2356G>A	p.Val786Ile	missense	Exon 18 of 18	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.2422G>A	p.Val808Ile	missense	Exon 19 of 19	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.2356G>A	p.Val786Ile	missense	Exon 18 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.00830 AC: 1263 AN: 152104 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00805 AC: 2008 AN: 249464 AF XY: 0.00799

Gnomad AFR exome AF: 0.00833

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00518

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00801

GnomAD4 exome AF: 0.0103 AC: 15005 AN: 1461144 Hom.: 96 Cov.: 32 AF XY: 0.00982 AC XY: 7138 AN XY: 726864

African (AFR) AF: 0.00747 AC: 250 AN: 33480

American (AMR) AF: 0.00150 AC: 67 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00589 AC: 154 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86256

European-Finnish (FIN) AF: 0.0166 AC: 874 AN: 52714

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0118 AC: 13176 AN: 1111988

Other (OTH) AF: 0.00758 AC: 458 AN: 60384

GnomAD4 genome AF: 0.00829 AC: 1262 AN: 152222 Hom.: 4 Cov.: 33 AF XY: 0.00842 AC XY: 627 AN XY: 74444

African (AFR) AF: 0.00768 AC: 319 AN: 41532

American (AMR) AF: 0.00170 AC: 26 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.0200 AC: 212 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0100 AC: 680 AN: 67978

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00935 Hom.: 24

Bravo AF: 0.00758

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00954 AC: 82

ExAC AF: 0.00850 AC: 1032

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00829

EpiControl AF: 0.00990

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Microcytic anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.2	L
PhyloP100		6.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.62
Sift	Benign	0.050	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.29
MVP		0.95
MPC		0.60
ClinPred		0.013	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.45
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139105452; hg19: chr22-37462173; COSMIC: COSV100696245; COSMIC: COSV100696245;