14-55043480-A-G

Position:

• chr14-55043480-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_199421.2(SOCS4):​c.439A>G​(p.Ile147Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 7.50

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36932063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOCS4	NM_199421.2	c.439A>G	p.Ile147Val	missense_variant	3/3	ENST00000555846.2	NP_955453.1
SOCS4	NM_080867.3	c.439A>G	p.Ile147Val	missense_variant	2/2		NP_543143.1
SOCS4	XM_011536425.2	c.439A>G	p.Ile147Val	missense_variant	3/3		XP_011534727.1
SOCS4	XM_011536426.2	c.439A>G	p.Ile147Val	missense_variant	3/3		XP_011534728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOCS4	ENST00000555846.2	c.439A>G	p.Ile147Val	missense_variant	3/3	1	NM_199421.2	ENSP00000452522.1
SOCS4	ENST00000339298.2	c.439A>G	p.Ile147Val	missense_variant	2/2	1		ENSP00000341327.2
SOCS4	ENST00000395472.2	c.439A>G	p.Ile147Val	missense_variant	2/2	1		ENSP00000378855.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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

Apr 11, 2023

The c.439A>G (p.I147V) alteration is located in exon 3 (coding exon 1) of the SOCS4 gene. This alteration results from a A to G substitution at nucleotide position 439, causing the isoleucine (I) at amino acid position 147 to be replaced by a valine (V). 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	.;.;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.035	D;D;D
Sift4G	Uncertain	0.054	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.43
MutPred		0.47		Gain of catalytic residue at R143 (P = 0);Gain of catalytic residue at R143 (P = 0);Gain of catalytic residue at R143 (P = 0);
MVP		0.78
MPC		0.52
ClinPred		0.70	D
GERP RS		5.8
Varity_R		0.12
gMVP		0.42

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: rs2042640241; hg19: chr14-55510198;