16-11254998-T-TGCGGC

Variant names:

• chr16-11254998-T-TGCGGC
• rs1470306246
• NM_003745.2:c.476_480dupGCCGC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_003745.2(SOCS1):​c.476_480dupGCCGC​(p.Met161AlafsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,415,538 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SOCS1 NM_003745.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.683

Genes affected

SOCS1 (HGNC:19383): (suppressor of cytokine signaling 1) This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by a subset of cytokines, including IL2, IL3 erythropoietin (EPO), CSF2/GM-CSF, and interferon (IFN)-gamma. The protein encoded by this gene functions downstream of cytokine receptors, and takes part in a negative feedback loop to attenuate cytokine signaling. Knockout studies in mice suggested the role of this gene as a modulator of IFN-gamma action, which is required for normal postnatal growth and survival. [provided by RefSeq, Jul 2008]

RMI2 (HGNC:28349): (RecQ mediated genome instability 2) RMI2 is a component of the BLM (RECQL3; MIM 604610) complex, which plays a role in homologous recombination-dependent DNA repair and is essential for genome stability (Xu et al., 2008 [PubMed 18923082]).[supplied by OMIM, Nov 2008]

LOC105371082 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.245 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-11254998-T-TGCGGC is Pathogenic according to our data. Variant chr16-11254998-T-TGCGGC is described in ClinVar as [Pathogenic]. Clinvar id is 977214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOCS1	NM_003745.2	c.476_480dupGCCGC	p.Met161AlafsTer46	frameshift_variant	Exon 2 of 2	ENST00000332029.4	NP_003736.1
LOC105371082	XR_933070.4	n.178+5228_178+5232dupGGCGC		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOCS1	ENST00000332029.4	c.476_480dupGCCGC	p.Met161AlafsTer46	frameshift_variant	Exon 2 of 2	1	NM_003745.2	ENSP00000329418.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000557 AC: 1 AN: 179392 Hom.: 0 AF XY: 0.00000996 AC XY: 1 AN XY: 100392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000552

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1415538 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 702468

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000200

Gnomad4 NFE exome AF: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoinflammatory syndrome with immunodeficiency Pathogenic:2

Jan 08, 2022

Department of Immunology, Beijing Children's Hospital of Capital Medical University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SOCS1 c.480_481insGCCGC (p.M161Afs*46) variant is classified as pathogenic based on it being a frameshift insertion predicted to result in a truncated or absent protein (PVS1), its rarity in population databases (PM2_Supporting), and published literature and ClinVar entries supporting its role in autoimmune disease (PS4). This variant is associated with autosomal dominant Autoimmune inflammatory syndrome, familial, with or without immunodeficiency (OMIM: 619375), which is characterized by a variety of autoimmune features. -

Jun 26, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 33087723). The variant has been reported to be associated with SOCS1 related disorder (ClinVar ID: VCV000977214 /PMID: 33087723). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Autoimmune hemolytic anemia;C0242584:Autoimmune thrombocytopenia Pathogenic:1

Jan 01, 2020

Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1470306246; hg19: chr16-11348855;