22-37073551-G-A

Variant names:

• chr22-37073551-G-A
• rs4820268
• NM_001374504.1:c.1536C>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.1536C>T​(p.Asp512Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,611,200 control chromosomes in the GnomAD database, including 237,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26621 hom., cov: 32)
  • Exomes 𝑓: 0.53 (210838 hom.)
• Consequence: TMPRSS6 NM_001374504.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.71
• Publications: 118 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=-0.68).
• BP6: Variant 22-37073551-G-A is Benign according to our data. Variant chr22-37073551-G-A is described in ClinVar as Benign. ClinVar VariationId is 262722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.724 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.1536C>T	p.Asp512Asp	synonymous	Exon 13 of 18	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.1536C>T	p.Asp512Asp	synonymous	Exon 13 of 19	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.1536C>T	p.Asp512Asp	synonymous	Exon 13 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.1536C>T	p.Asp512Asp	synonymous	Exon 13 of 18	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1536C>T	p.Asp512Asp	synonymous	Exon 13 of 19	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.1536C>T	p.Asp512Asp	synonymous	Exon 13 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88477 AN: 151916 Hom.: 26588 Cov.: 32

Gnomad AFR AF: 0.731

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.555

GnomAD2 exomes AF: 0.535 AC: 134439 AN: 251322 AF XY: 0.528

Gnomad AFR exome AF: 0.736

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.538

Gnomad EAS exome AF: 0.473

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.535 AC: 780612 AN: 1459166 Hom.: 210838 Cov.: 35 AF XY: 0.533 AC XY: 386683 AN XY: 726054

African (AFR) AF: 0.736 AC: 24605 AN: 33428

American (AMR) AF: 0.504 AC: 22523 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 13924 AN: 26106

East Asian (EAS) AF: 0.460 AC: 18240 AN: 39690

South Asian (SAS) AF: 0.454 AC: 39168 AN: 86204

European-Finnish (FIN) AF: 0.574 AC: 30601 AN: 53302

Middle Eastern (MID) AF: 0.556 AC: 3202 AN: 5760

European-Non Finnish (NFE) AF: 0.537 AC: 595969 AN: 1109640

Other (OTH) AF: 0.537 AC: 32380 AN: 60314

GnomAD4 genome AF: 0.582 AC: 88552 AN: 152034 Hom.: 26621 Cov.: 32 AF XY: 0.575 AC XY: 42754 AN XY: 74318

African (AFR) AF: 0.731 AC: 30323 AN: 41478

American (AMR) AF: 0.484 AC: 7402 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1917 AN: 3466

East Asian (EAS) AF: 0.466 AC: 2407 AN: 5164

South Asian (SAS) AF: 0.434 AC: 2093 AN: 4820

European-Finnish (FIN) AF: 0.564 AC: 5958 AN: 10568

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36588 AN: 67950

Other (OTH) AF: 0.548 AC: 1154 AN: 2104

Alfa AF: 0.550 Hom.: 92346

Bravo AF: 0.588

Asia WGS AF: 0.413 AC: 1435 AN: 3478

EpiCase AF: 0.543

EpiControl AF: 0.536

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Iron-refractory iron deficiency anemia (2)
-	-	1	Microcytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.020
DANN	Benign	0.35
PhyloP100		-1.7
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4820268; hg19: chr22-37469591; COSMIC: COSV60976234;