NM_003955.5:c.128A>G

Variant names:

• chr17-78358968-T-C
• rs1211975469
• NM_003955.5:c.128A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003955.5(SOCS3):​c.128A>G​(p.Glu43Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,430,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SOCS3 NM_003955.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79
• Publications: 0 publications found

Genes affected

SOCS3 (HGNC:19391): (suppressor of cytokine signaling 3) 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 is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma. The protein encoded by this gene can bind to JAK2 kinase, and inhibit the activity of JAK2 kinase. Studies of the mouse counterpart of this gene suggested the roles of this gene in the negative regulation of fetal liver hematopoiesis, and placental development. [provided by RefSeq, Jul 2008]

SOCS3-DT (HGNC:52799): (SOCS3 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36078113).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003955.5. 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
	SOCS3	NM_003955.5	MANE Select	c.128A>G	p.Glu43Gly	missense	Exon 2 of 2	NP_003946.3
	SOCS3	NM_001378932.1		c.128A>G	p.Glu43Gly	missense	Exon 2 of 2	NP_001365861.1	O14543
	SOCS3	NM_001378933.1		c.128A>G	p.Glu43Gly	missense	Exon 2 of 2	NP_001365862.1	O14543

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOCS3	ENST00000330871.3	TSL:1 MANE Select	c.128A>G	p.Glu43Gly	missense	Exon 2 of 2	ENSP00000330341.2	O14543
	SOCS3	ENST00000907726.1		c.128A>G	p.Glu43Gly	missense	Exon 2 of 2	ENSP00000577785.1
	SOCS3	ENST00000912407.1		c.128A>G	p.Glu43Gly	missense	Exon 3 of 3	ENSP00000582466.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000102 AC: 2 AN: 196858 AF XY: 0.00000938

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000701

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1430680 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708980

African (AFR) AF: 0.00 AC: 0 AN: 32934

American (AMR) AF: 0.0000505 AC: 2 AN: 39596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25454

East Asian (EAS) AF: 0.00 AC: 0 AN: 38288

South Asian (SAS) AF: 0.00 AC: 0 AN: 82420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097008

Other (OTH) AF: 0.00 AC: 0 AN: 59236

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	0.077
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.19
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.024	D
Polyphen		0.60	P
Vest4		0.37
MutPred		0.42		Gain of catalytic residue at E43 (P = 0.0039)
MVP		0.36
MPC		1.6
ClinPred		0.56	D
GERP RS		4.2
Varity_R		0.62
gMVP		0.70

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: rs1211975469; hg19: chr17-76355049;