rs116690692

chr5-95482498-T-Cchr5-95482498-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014639.4(SKIC3):c.4187A>G(p.Asn1396Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,613,930 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (57 hom.)
• Consequence: SKIC3 NM_014639.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.43

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007912427).
• BP6: Variant 5-95482498-T-C is Benign according to our data. Variant chr5-95482498-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235756.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0051 (777/152238) while in subpopulation NFE AF= 0.00718 (488/67992). AF 95% confidence interval is 0.00665. There are 1 homozygotes in gnomad4. There are 363 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKIC3	NM_014639.4	c.4187A>G	p.Asn1396Ser	missense_variant	39/43	ENST00000358746.7
SKIC3	XM_047417937.1	c.4187A>G	p.Asn1396Ser	missense_variant	39/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKIC3	ENST00000358746.7	c.4187A>G	p.Asn1396Ser	missense_variant	39/43	1	NM_014639.4	P4

Frequencies

GnomAD3 genomes AF: 0.00510 AC: 776 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00718

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00548 AC: 1378 AN: 251404 Hom.: 6 AF XY: 0.00580 AC XY: 788 AN XY: 135870

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00676

Gnomad FIN exome AF: 0.00707

Gnomad NFE exome AF: 0.00744

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00764 AC: 11168 AN: 1461692 Hom.: 57 Cov.: 31 AF XY: 0.00764 AC XY: 5559 AN XY: 727154

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00666

Gnomad4 FIN exome AF: 0.00702

Gnomad4 NFE exome AF: 0.00866

Gnomad4 OTH exome AF: 0.00566

GnomAD4 genome AF: 0.00510 AC: 777 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00488 AC XY: 363 AN XY: 74454

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00678

Gnomad4 NFE AF: 0.00718

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00622 Hom.: 6

Bravo AF: 0.00519

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00539 AC: 655

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00742

EpiControl AF: 0.00800

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Oct 28, 2022	TTC37 NM_014639.3 exon 39 p.Asn1396Ser (c.4187A>G): This variant has not been reported in the literature, but is present in 0.7% (944/129130) of European alleles, including 2 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-94818202-T-C). This variant is present in ClinVar (Variation ID:235756). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant suggests that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SKIC3: BP4, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0046	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.43	T
Polyphen		0.13	B;B
Vest4		0.21
MVP		0.71
MPC		0.10
ClinPred		0.0074	T
GERP RS		5.7
Varity_R		0.088
gMVP		0.36

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: rs116690692; hg19: chr5-94818202;