chr22-37065994-G-A

Position:

• chr22-37065994-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374504.1(TMPRSS6):​c.*86C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,557,390 control chromosomes in the GnomAD database, including 603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (133 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (470 hom.)
• Consequence: TMPRSS6 NM_001374504.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00300

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-37065994-G-A is Benign according to our data. Variant chr22-37065994-G-A is described in ClinVar as [Benign]. Clinvar id is 341575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS6	NM_001374504.1	c.*86C>T		3_prime_UTR_variant	18/18	ENST00000676104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.*86C>T		3_prime_UTR_variant	18/18		NM_001374504.1	P1

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3577 AN: 151552 Hom.: 132 Cov.: 33

Gnomad AFR AF: 0.0699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00828

Gnomad ASJ AF: 0.00838

Gnomad EAS AF: 0.00272

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000604

Gnomad OTH AF: 0.0173

GnomAD4 exome AF: 0.00792 AC: 11132 AN: 1405720 Hom.: 470 Cov.: 25 AF XY: 0.0101 AC XY: 7038 AN XY: 700062

Gnomad4 AFR exome AF: 0.0684

Gnomad4 AMR exome AF: 0.00493

Gnomad4 ASJ exome AF: 0.00763

Gnomad4 EAS exome AF: 0.00136

Gnomad4 SAS exome AF: 0.0862

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000401

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0237 AC: 3594 AN: 151670 Hom.: 133 Cov.: 33 AF XY: 0.0246 AC XY: 1822 AN XY: 74074

Gnomad4 AFR AF: 0.0701

Gnomad4 AMR AF: 0.00826

Gnomad4 ASJ AF: 0.00838

Gnomad4 EAS AF: 0.00273

Gnomad4 SAS AF: 0.0930

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000604

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.0167 Hom.: 5

Bravo AF: 0.0241

Asia WGS AF: 0.0560 AC: 194 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs116795891; hg19: chr22-37462034;