rs2303650

chr5-95490951-C-Achr5-95490951-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014639.4(SKIC3):c.3888G>T(p.Arg1296Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,613,666 control chromosomes in the GnomAD database, including 24,529 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (4659 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19870 hom.)
• Consequence: SKIC3 NM_014639.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33

Genes affected

SKIC3 (HGNC:23639): (SKI3 subunit of superkiller complex) This gene encodes a protein with twenty tetratricopeptide (TPR) repeats. Tetratricopeptide repeat containing motifs are found in a variety of proteins and may mediate protein-protein interactions and chaperone activity. Mutations in this gene are associated with trichohepatoenteric syndrome. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020938218).
• BP6: Variant 5-95490951-C-A is Benign according to our data. Variant chr5-95490951-C-A is described in ClinVar as [Benign]. Clinvar id is 1166551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKIC3	NM_014639.4	c.3888G>T	p.Arg1296Ser	missense_variant	37/43	ENST00000358746.7
SKIC3	XM_047417937.1	c.3888G>T	p.Arg1296Ser	missense_variant	37/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKIC3	ENST00000358746.7	c.3888G>T	p.Arg1296Ser	missense_variant	37/43	1	NM_014639.4	P4

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33494 AN: 151882 Hom.: 4648 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.226

GnomAD3 exomes AF: 0.179 AC: 44893 AN: 251232 Hom.: 4818 AF XY: 0.177 AC XY: 24052 AN XY: 135830

Gnomad AFR exome AF: 0.395

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.335

Gnomad EAS exome AF: 0.123

Gnomad SAS exome AF: 0.198

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.155 AC: 226758 AN: 1461666 Hom.: 19870 Cov.: 33 AF XY: 0.157 AC XY: 114319 AN XY: 727144

Gnomad4 AFR exome AF: 0.395

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.327

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.221 AC: 33533 AN: 152000 Hom.: 4659 Cov.: 32 AF XY: 0.219 AC XY: 16312 AN XY: 74320

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.326

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.223

Alfa AF: 0.169 Hom.: 6163

Bravo AF: 0.233

TwinsUK AF: 0.134 AC: 498

ALSPAC AF: 0.128 AC: 493

ESP6500AA AF: 0.374 AC: 1648

ESP6500EA AF: 0.159 AC: 1367

ExAC AF: 0.182 AC: 22103

Asia WGS AF: 0.123 AC: 428 AN: 3478

EpiCase AF: 0.170

EpiControl AF: 0.170

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Trichohepatoenteric syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.12	P
PrimateAI	Benign	0.40	T
Polyphen		0.70	P;P
Vest4		0.24
MutPred		0.38		Gain of ubiquitination at K1295 (P = 0.0638);Gain of ubiquitination at K1295 (P = 0.0638);
MPC		0.19
ClinPred		0.022	T
GERP RS		3.2
Varity_R		0.27
gMVP		0.66

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: rs2303650; hg19: chr5-94826655; COSMIC: COSV62454813;