chr16-11254875-C-T

Variant names:

• chr16-11254875-C-T
• rs2141124229
• NM_003745.2:c.604G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003745.2(SOCS1):​c.604G>A​(p.Asp202Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000224 in 1,338,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D202Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SOCS1 NM_003745.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003745.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOCS1	NM_003745.2	MANE Select	c.604G>A	p.Asp202Asn	missense	Exon 2 of 2	NP_003736.1	Q4JHT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOCS1	ENST00000332029.4	TSL:1 MANE Select	c.604G>A	p.Asp202Asn	missense	Exon 2 of 2	ENSP00000329418.2	O15524
	RMI2	ENST00000572173.1	TSL:1	c.-516+5097C>T		intron	N/A	ENSP00000461206.1	Q96E14-2
	SOCS1	ENST00000644787.2		c.604G>A	p.Asp202Asn	missense	Exon 1 of 1	ENSP00000496577.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000224 AC: 3 AN: 1338808 Hom.: 0 Cov.: 32 AF XY: 0.00000302 AC XY: 2 AN XY: 662306

African (AFR) AF: 0.00 AC: 0 AN: 26244

American (AMR) AF: 0.00 AC: 0 AN: 21318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19602

East Asian (EAS) AF: 0.00 AC: 0 AN: 32644

South Asian (SAS) AF: 0.00 AC: 0 AN: 67078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49860

Middle Eastern (MID) AF: 0.000189 AC: 1 AN: 5288

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1062068

Other (OTH) AF: 0.00 AC: 0 AN: 54706

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autoinflammatory syndrome with immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.21
Sift	Benign	0.043	D
Sift4G	Benign	0.19	T
Polyphen		0.89	P
Vest4		0.38
MutPred		0.61		Gain of helix (P = 0.0854)
MVP		0.67
MPC		1.3
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.41
gMVP		0.49
Mutation Taster		=60/40	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: rs2141124229; hg19: chr16-11348732;