chr22-37065994-G-A

Variant names:

• chr22-37065994-G-A
• rs116795891
• NM_001374504.1:c.*86C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.*86C>T		3_prime_UTR_variant	Exon 18 of 18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.*86C>T		3_prime_UTR_variant	Exon 18 of 18		NM_001374504.1	ENSP00000501573.1

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

African (AFR) AF: 0.0684 AC: 2211 AN: 32318

American (AMR) AF: 0.00493 AC: 218 AN: 44238

Ashkenazi Jewish (ASJ) AF: 0.00763 AC: 195 AN: 25548

East Asian (EAS) AF: 0.00136 AC: 53 AN: 38986

South Asian (SAS) AF: 0.0862 AC: 7272 AN: 84336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50860

Middle Eastern (MID) AF: 0.00873 AC: 40 AN: 4580

European-Non Finnish (NFE) AF: 0.000401 AC: 428 AN: 1066580

Other (OTH) AF: 0.0123 AC: 715 AN: 58274

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

African (AFR) AF: 0.0701 AC: 2896 AN: 41310

American (AMR) AF: 0.00826 AC: 126 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00838 AC: 29 AN: 3460

East Asian (EAS) AF: 0.00273 AC: 14 AN: 5136

South Asian (SAS) AF: 0.0930 AC: 447 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000604 AC: 41 AN: 67860

Other (OTH) AF: 0.0171 AC: 36 AN: 2104

Alfa AF: 0.0186 Hom.: 6

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.51
PhyloP100		-0.0030
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs116795891; hg19: chr22-37462034;