rs79816125

Positions:

• chr22-37074600-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374504.1(TMPRSS6):​c.1441+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,613,528 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 33)
  • Exomes 𝑓: 0.016 (206 hom.)
• Consequence: TMPRSS6 NM_001374504.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.402

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 22-37074600-G-A is Benign according to our data. Variant chr22-37074600-G-A is described in ClinVar as [Benign]. Clinvar id is 262721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1839/152308) while in subpopulation NFE AF= 0.0171 (1166/68022). AF 95% confidence interval is 0.0163. There are 22 homozygotes in gnomad4. There are 906 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.1441+10C>T		intron_variant		ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.1441+10C>T		intron_variant			NM_001374504.1	ENSP00000501573	P1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1839 AN: 152190 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0115 AC: 2893 AN: 250666 Hom.: 36 AF XY: 0.0120 AC XY: 1626 AN XY: 135620

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.00921

Gnomad ASJ exome AF: 0.00607

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0156 AC: 22778 AN: 1461220 Hom.: 206 Cov.: 32 AF XY: 0.0152 AC XY: 11086 AN XY: 726982

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.00651

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.0183

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0121 AC: 1839 AN: 152308 Hom.: 22 Cov.: 33 AF XY: 0.0122 AC XY: 906 AN XY: 74466

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0127 Hom.: 9

Bravo AF: 0.0117

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 17, 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 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.32

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: rs79816125; hg19: chr22-37470640;