Genetic Variant SOCS1:p.Gln210His (chr16-11254849-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003745.2(SOCS1):c.630G>T(p.Gln210His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000754 in 1,325,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q210R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

SOCS1
NM_003745.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.92

Publications

0 publications found

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 was made for transcript

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=0.3061394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOCS1	NM_003745.2 link	c.630G>T	p.Gln210His	missense_variant	Exon 2 of 2	ENST00000332029.4	NP_003736.1	O15524Q4JHT5
LOC105371082	XR_933070.4 link	n.178+5071C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOCS1	ENST00000332029.4 link	c.630G>T	p.Gln210His	missense_variant	Exon 2 of 2	1	NM_003745.2	ENSP00000329418.2		O15524

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.54e-7

AC:

AN:

1325932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

654228

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25874

American (AMR)

AF:

0.00

AC:

AN:

20414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18660

East Asian (EAS)

AF:

0.00

AC:

AN:

32574

South Asian (SAS)

AF:

0.0000154

AC:

AN:

64904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5222

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1054738

Other (OTH)

AF:

0.00

AC:

AN:

54068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;D

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.57

.;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

PhyloP100

1.9

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.070

Sift

Benign

0.068

T;.

Sift4G

Benign

0.065

T;.

Polyphen

0.97

D;D

Vest4

0.14

MutPred

0.12

Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);

MVP

0.66

MPC

1.5

ClinPred

0.80

GERP RS

4.4

Varity_R

0.15

gMVP

0.46

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over