rs2235321

Positions:

• chr22-37066886-G-A
• chr22-37066886-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001374504.1(TMPRSS6):​c.2190C>T​(p.Tyr730=) variant causes a synonymous change. The variant allele was found at a frequency of 0.378 in 1,613,618 control chromosomes in the GnomAD database, including 117,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11343 hom., cov: 33)
  • Exomes 𝑓: 0.38 (106165 hom.)
• Consequence: TMPRSS6 NM_001374504.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.74

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 22-37066886-G-A is Benign according to our data. Variant chr22-37066886-G-A is described in ClinVar as [Benign]. Clinvar id is 262726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37066886-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.2190C>T	p.Tyr730=	synonymous_variant	17/18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.2190C>T	p.Tyr730=	synonymous_variant	17/18		NM_001374504.1	ENSP00000501573	P1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58137 AN: 151890 Hom.: 11330 Cov.: 33

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.363

GnomAD3 exomes AF: 0.360 AC: 90277 AN: 250550 Hom.: 16899 AF XY: 0.359 AC XY: 48723 AN XY: 135614

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.351

Gnomad EAS exome AF: 0.442

Gnomad SAS exome AF: 0.283

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.377 AC: 551480 AN: 1461610 Hom.: 106165 Cov.: 55 AF XY: 0.375 AC XY: 272372 AN XY: 727094

Gnomad4 AFR exome AF: 0.421

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.351

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.287

Gnomad4 FIN exome AF: 0.478

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.383 AC: 58180 AN: 152008 Hom.: 11343 Cov.: 33 AF XY: 0.381 AC XY: 28328 AN XY: 74290

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.272

Gnomad4 FIN AF: 0.478

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.360

Alfa AF: 0.364 Hom.: 16458

Bravo AF: 0.374

Asia WGS AF: 0.290 AC: 1008 AN: 3478

EpiCase AF: 0.381

EpiControl AF: 0.368

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Microcytic anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.4
DANN	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs2235321; hg19: chr22-37462926; COSMIC: COSV60976213; COSMIC: COSV60976213;