Genetic Variant NM_003745.2:c.604G>A (chr16-11254875-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

SOCS1
NM_003745.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62

Variant links:

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]

SOCS1 links:

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]

RMI2 links:

LOC105371082 (HGNC:):

LOC105371082 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOCS1	NM_003745.2 link	c.604G>A	p.Asp202Asn	missense_variant	Exon 2 of 2	ENST00000332029.4	NP_003736.1	O15524Q4JHT5
LOC105371082	XR_933070.4 link	n.178+5097C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOCS1	ENST00000332029.4 link	c.604G>A	p.Asp202Asn	missense_variant	Exon 2 of 2	1	NM_003745.2	ENSP00000329418.2		O15524

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000224

AC:

AN:

1338808

Hom.:

Cov.:

AF XY:

0.00000302

AC XY:

AN XY:

662306

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.00000188

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autoinflammatory syndrome with immunodeficiency

Uncertain:1

Dec 02, 2024

Paediatric Laboratory, Institute for Maternal and Child Health - IRCCS Burlo Garofolo

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_003745.2:c.604G>A variant is predicted to cause the substitution of the aspartic acid residue at position 202 with an asparagine. This variant has been identified in three individuals in the gnomAD v4.1.0 database but has not been previously reported in ClinVar or LOVD. It does not meet any ACMG criteria for either pathogenicity or benign impact, and is thus classified as a variant of unknown significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;D

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.3

L;L

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.0

D;.

REVEL

Benign

0.21

Sift

Benign

0.043

D;.

Sift4G

Benign

0.19

T;.

Polyphen

0.89

P;P

Vest4

0.38

MutPred

0.61

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.67

MPC

1.3

ClinPred

0.95

GERP RS

4.3

Varity_R

0.41

gMVP

0.49

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over