NM_001374504.1:c.1227C>T

Variant names:

• chr22-37075250-G-A
• rs881144
• NM_001374504.1:c.1227C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001374504.1(TMPRSS6):​c.1227C>T​(p.Tyr409Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,600 control chromosomes in the GnomAD database, including 10,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (667 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9337 hom.)
• Consequence: TMPRSS6 NM_001374504.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.868
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 22-37075250-G-A is Benign according to our data. Variant chr22-37075250-G-A is described in ClinVar as Benign. ClinVar VariationId is 262720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.868 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 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.1227C>T	p.Tyr409Tyr	synonymous	Exon 11 of 18	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.1227C>T	p.Tyr409Tyr	synonymous	Exon 11 of 19	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.1227C>T	p.Tyr409Tyr	synonymous	Exon 11 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.1227C>T	p.Tyr409Tyr	synonymous	Exon 11 of 18	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1227C>T	p.Tyr409Tyr	synonymous	Exon 11 of 19	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.1227C>T	p.Tyr409Tyr	synonymous	Exon 11 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12455 AN: 152172 Hom.: 665 Cov.: 33

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0692

Gnomad ASJ AF: 0.0746

Gnomad EAS AF: 0.0431

Gnomad SAS AF: 0.0379

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.0869

GnomAD2 exomes AF: 0.0893 AC: 22323 AN: 249996 AF XY: 0.0903

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.0524

Gnomad ASJ exome AF: 0.0790

Gnomad EAS exome AF: 0.0498

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.109 AC: 159533 AN: 1461310 Hom.: 9337 Cov.: 35 AF XY: 0.107 AC XY: 78029 AN XY: 726974

African (AFR) AF: 0.0176 AC: 590 AN: 33480

American (AMR) AF: 0.0549 AC: 2454 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0809 AC: 2115 AN: 26136

East Asian (EAS) AF: 0.0369 AC: 1463 AN: 39700

South Asian (SAS) AF: 0.0435 AC: 3748 AN: 86258

European-Finnish (FIN) AF: 0.140 AC: 7409 AN: 52860

Middle Eastern (MID) AF: 0.0709 AC: 409 AN: 5768

European-Non Finnish (NFE) AF: 0.122 AC: 135320 AN: 1111998

Other (OTH) AF: 0.0998 AC: 6025 AN: 60386

GnomAD4 genome AF: 0.0818 AC: 12462 AN: 152290 Hom.: 667 Cov.: 33 AF XY: 0.0819 AC XY: 6097 AN XY: 74442

African (AFR) AF: 0.0228 AC: 948 AN: 41582

American (AMR) AF: 0.0691 AC: 1057 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0746 AC: 259 AN: 3472

East Asian (EAS) AF: 0.0436 AC: 226 AN: 5186

South Asian (SAS) AF: 0.0390 AC: 188 AN: 4826

European-Finnish (FIN) AF: 0.149 AC: 1583 AN: 10592

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7961 AN: 68008

Other (OTH) AF: 0.0865 AC: 183 AN: 2116

Alfa AF: 0.0862 Hom.: 617

Bravo AF: 0.0743

Asia WGS AF: 0.0410 AC: 144 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.117

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Iron-refractory iron deficiency anemia (1)
-	-	1	Microcytic anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.10
DANN	Benign	0.88
PhyloP100		-0.87
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: rs881144; hg19: chr22-37471290; COSMIC: COSV60975501; COSMIC: COSV60975501;