16-11254849-C-G

Position:

chr16-11254849-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003745.2(SOCS1):c.630G>C(p.Gln210His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,478,218 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0053 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0093 ( 69 hom. )

Consequence

SOCS1
NM_003745.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 1.92

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009278804).

BP6

Variant 16-11254849-C-G is Benign according to our data. Variant chr16-11254849-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 135275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00534 (813/152302) while in subpopulation NFE AF= 0.00922 (627/68018). AF 95% confidence interval is 0.00862. There are 4 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 813 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOCS1	NM_003745.2 linkuse as main transcript	c.630G>C	p.Gln210His	missense_variant	2/2	ENST00000332029.4
LOC105371082	XR_933070.4 linkuse as main transcript	n.178+5071C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOCS1	ENST00000332029.4 linkuse as main transcript	c.630G>C	p.Gln210His	missense_variant	2/2	1	NM_003745.2	P1

Frequencies

GnomAD3 genomes

AF:

0.00534

AC:

813

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00922

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00498

AC:

642

AN:

128918

Hom.:

AF XY:

0.00487

AC XY:

346

AN XY:

71056

show subpopulations

Gnomad AFR exome

AF:

0.00239

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.000771

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000482

Gnomad FIN exome

AF:

0.00227

Gnomad NFE exome

AF:

0.00802

Gnomad OTH exome

AF:

0.00421

GnomAD4 exome

AF:

0.00925

AC:

12270

AN:

1325916

Hom.:

Cov.:

AF XY:

0.00882

AC XY:

5773

AN XY:

654216

show subpopulations

Gnomad4 AFR exome

AF:

0.00151

Gnomad4 AMR exome

AF:

0.00142

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000632

Gnomad4 FIN exome

AF:

0.00234

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.00520

GnomAD4 genome

AF:

0.00534

AC:

813

AN:

152302

Hom.:

Cov.:

AF XY:

0.00450

AC XY:

335

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.00922

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00815

Hom.:

Bravo

AF:

0.00571

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00229

AC:

ESP6500EA

AF:

0.00854

AC:

ExAC

AF:

0.00435

AC:

525

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	RMI2: BS2; SOCS1: BS2 -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;D

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.57

.;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0093

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.059

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

0.012

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over