rs11549428

chr16-11254849-C-Gchr16-11254849-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.92

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

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 813 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOCS1	NM_003745.2	c.630G>C	p.Gln210His	missense_variant	2/2	ENST00000332029.4
LOC105371082	XR_933070.4	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	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.: 4 Cov.: 33

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.: 4 AF XY: 0.00487 AC XY: 346 AN XY: 71056

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.: 69 Cov.: 32 AF XY: 0.00882 AC XY: 5773 AN XY: 654216

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.: 4 Cov.: 33 AF XY: 0.00450 AC XY: 335 AN XY: 74488

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.: 2

Bravo AF: 0.00571

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00229 AC: 10

ESP6500EA AF: 0.00854 AC: 73

ExAC AF: 0.00435 AC: 525

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 20, 2018	- -
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	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
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	T
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

Other links and lift over

dbSNP: rs11549428; hg19: chr16-11348706; COSMIC: COSV59659165;