rs140408537

Variant names:

• chr1-150747785-C-A
• rs140408537
• NM_004079.5:c.888G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-150747785-C-A
• chr1-150747785-C-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_004079.5(CTSS):​c.888G>T​(p.Val296Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,606,942 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0091 (88 hom.)
• Consequence: CTSS NM_004079.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.455
• Publications: 3 publications found

Genes affected

CTSS (HGNC:2545): (cathepsin S) The preproprotein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that participates in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules. The mature protein cleaves the invariant chain of MHC class II molecules in endolysosomal compartments and enables the formation of antigen-MHC class II complexes and the proper display of extracellular antigenic peptides by MHC-II. The mature protein also functions as an elastase over a broad pH range. When secreted from cells, this protein can remodel components of the extracellular matrix such as elastin, collagen, and fibronectin. This gene is implicated in the pathology of many inflammatory and autoimmune diseases and, given its elastase activity, plays a significant role in some pulmonary diseases. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2020]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 1-150747785-C-A is Benign according to our data. Variant chr1-150747785-C-A is described in ClinVar as [Benign]. Clinvar id is 777937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.455 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSS	NM_004079.5	c.888G>T	p.Val296Val	synonymous_variant	Exon 7 of 8	ENST00000368985.8	NP_004070.3
CTSS	NM_001199739.2	c.738G>T	p.Val246Val	synonymous_variant	Exon 6 of 7		NP_001186668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSS	ENST00000368985.8	c.888G>T	p.Val296Val	synonymous_variant	Exon 7 of 8	1	NM_004079.5	ENSP00000357981.3

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 950 AN: 152056 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00641 AC: 1602 AN: 250050 AF XY: 0.00636

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.000703

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00907 AC: 13188 AN: 1454768 Hom.: 88 Cov.: 28 AF XY: 0.00878 AC XY: 6357 AN XY: 724186

African (AFR) AF: 0.00135 AC: 45 AN: 33266

American (AMR) AF: 0.000633 AC: 28 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85748

European-Finnish (FIN) AF: 0.0128 AC: 681 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0109 AC: 12031 AN: 1106488

Other (OTH) AF: 0.00607 AC: 365 AN: 60136

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152174 Hom.: 8 Cov.: 31 AF XY: 0.00668 AC XY: 497 AN XY: 74404

African (AFR) AF: 0.00159 AC: 66 AN: 41514

American (AMR) AF: 0.00144 AC: 22 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0104 AC: 708 AN: 68008

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00712 Hom.: 2

Bravo AF: 0.00544

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00836

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.9
DANN	Benign	0.77
PhyloP100		0.46
Mutation Taster		=92/8	polymorphism

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: rs140408537; hg19: chr1-150720261;