14-55043212-A-T

Position:

• chr14-55043212-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_199421.2(SOCS4):​c.171A>T​(p.Lys57Asn) 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 1,461,882 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: 0.905

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05432573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOCS4	NM_199421.2	c.171A>T	p.Lys57Asn	missense_variant	3/3	ENST00000555846.2	NP_955453.1
SOCS4	NM_080867.3	c.171A>T	p.Lys57Asn	missense_variant	2/2		NP_543143.1
SOCS4	XM_011536425.2	c.171A>T	p.Lys57Asn	missense_variant	3/3		XP_011534727.1
SOCS4	XM_011536426.2	c.171A>T	p.Lys57Asn	missense_variant	3/3		XP_011534728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOCS4	ENST00000555846.2	c.171A>T	p.Lys57Asn	missense_variant	3/3	1	NM_199421.2	ENSP00000452522.1
SOCS4	ENST00000339298.2	c.171A>T	p.Lys57Asn	missense_variant	2/2	1		ENSP00000341327.2
SOCS4	ENST00000395472.2	c.171A>T	p.Lys57Asn	missense_variant	2/2	1		ENSP00000378855.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

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

Dec 13, 2023

The c.171A>T (p.K57N) alteration is located in exon 3 (coding exon 1) of the SOCS4 gene. This alteration results from a A to T substitution at nucleotide position 171, causing the lysine (K) at amino acid position 57 to be replaced by an asparagine (N). 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	0.093
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.1
DANN	Benign	0.88
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.68	.;.;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.13	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.048
MutPred		0.32		Loss of ubiquitination at K57 (P = 9e-04);Loss of ubiquitination at K57 (P = 9e-04);Loss of ubiquitination at K57 (P = 9e-04);
MVP		0.32
MPC		0.14
ClinPred		0.074	T
GERP RS		1.4
Varity_R		0.034
gMVP		0.076

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: rs2042636192; hg19: chr14-55509930;