rs114914951

Positions:

• chr5-95543288-C-T

Variant summary

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

The ENST00000358746.7(SKIC3):​c.130G>A​(p.Val44Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,613,950 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (34 hom.)
• Consequence: SKIC3 ENST00000358746.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.52

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=0.0063295364).
• BP6: Variant 5-95543288-C-T is Benign according to our data. Variant chr5-95543288-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-95543288-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1864/152184) while in subpopulation AFR AF= 0.0418 (1733/41508). AF 95% confidence interval is 0.0401. There are 39 homozygotes in gnomad4. There are 895 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKIC3	NM_014639.4	c.130G>A	p.Val44Ile	missense_variant	5/43	ENST00000358746.7	NP_055454.1
SKIC3	XM_047417937.1	c.130G>A	p.Val44Ile	missense_variant	5/43		XP_047273893.1
SKIC3	XM_047417938.1	c.130G>A	p.Val44Ile	missense_variant	5/29		XP_047273894.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKIC3	ENST00000358746.7	c.130G>A	p.Val44Ile	missense_variant	5/43	1	NM_014639.4	ENSP00000351596	P4

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1853 AN: 152066 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00348 AC: 874 AN: 251370 Hom.: 15 AF XY: 0.00269 AC XY: 365 AN XY: 135854

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00139 AC: 2035 AN: 1461766 Hom.: 34 Cov.: 32 AF XY: 0.00126 AC XY: 914 AN XY: 727190

Gnomad4 AFR exome AF: 0.0374

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000273

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.0122 AC: 1864 AN: 152184 Hom.: 39 Cov.: 32 AF XY: 0.0120 AC XY: 895 AN XY: 74374

Gnomad4 AFR AF: 0.0418

Gnomad4 AMR AF: 0.00465

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00250 Hom.: 7

Bravo AF: 0.0141

ESP6500AA AF: 0.0427 AC: 188

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00394 AC: 478

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;D
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.52	.;N;N
REVEL	Benign	0.17
Sift	Benign	0.13	.;T;T
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		0.99	D;D;.
Vest4		0.64
MVP		0.37
MPC		0.39
ClinPred		0.012	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.32

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: rs114914951; hg19: chr5-94878992;