14-55043532-C-G

Position:

• chr14-55043532-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199421.2(SOCS4):​c.491C>G​(p.Thr164Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SOCS4 NM_199421.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

Genes affected

SOCS4 (HGNC:19392): (suppressor of cytokine signaling 4) The protein encoded by this gene contains a SH2 domain and a SOCS BOX domain. The protein thus belongs to the suppressor of cytokine signaling (SOCS), also known as STAT-induced STAT inhibitor (SSI), protein family. SOCS family members are known to be cytokine-inducible negative regulators of cytokine signaling. Two alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14041838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOCS4	NM_199421.2	c.491C>G	p.Thr164Arg	missense_variant	3/3	ENST00000555846.2	NP_955453.1
SOCS4	NM_080867.3	c.491C>G	p.Thr164Arg	missense_variant	2/2		NP_543143.1
SOCS4	XM_011536425.2	c.491C>G	p.Thr164Arg	missense_variant	3/3		XP_011534727.1
SOCS4	XM_011536426.2	c.491C>G	p.Thr164Arg	missense_variant	3/3		XP_011534728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOCS4	ENST00000555846.2	c.491C>G	p.Thr164Arg	missense_variant	3/3	1	NM_199421.2	ENSP00000452522.1
SOCS4	ENST00000339298.2	c.491C>G	p.Thr164Arg	missense_variant	2/2	1		ENSP00000341327.2
SOCS4	ENST00000395472.2	c.491C>G	p.Thr164Arg	missense_variant	2/2	1		ENSP00000378855.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.491C>G (p.T164R) alteration is located in exon 3 (coding exon 1) of the SOCS4 gene. This alteration results from a C to G substitution at nucleotide position 491, causing the threonine (T) at amino acid position 164 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	.;.;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.099	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.66	P;P;P
Vest4		0.22
MutPred		0.31		Gain of catalytic residue at T164 (P = 0.0426);Gain of catalytic residue at T164 (P = 0.0426);Gain of catalytic residue at T164 (P = 0.0426);
MVP		0.65
MPC		0.18
ClinPred		0.18	T
GERP RS		4.6
Varity_R		0.059
gMVP		0.31

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.

Other links and lift over

hg19: chr14-55510250;