rs116690692

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.43

Variant links:

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]

SKIC3 links:

SKIC3 (HGNC:):

SKIC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, Uncertain_significance=1, Benign=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 GnomAdExome4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKIC3	NM_014639.4 linkuse as main transcript	c.4187A>G	p.Asn1396Ser	missense_variant	39/43	ENST00000358746.7	NP_055454.1	Q6PGP7
SKIC3	XM_047417937.1 linkuse as main transcript	c.4187A>G	p.Asn1396Ser	missense_variant	39/43		XP_047273893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKIC3	ENST00000358746.7 linkuse as main transcript	c.4187A>G	p.Asn1396Ser	missense_variant	39/43	1	NM_014639.4	ENSP00000351596.3		Q6PGP7

Frequencies

GnomAD3 genomes

AF:

0.00510

AC:

776

AN:

152120

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00580

AC XY:

788

AN XY:

135870

show subpopulations

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.:

Cov.:

AF XY:

0.00764

AC XY:

5559

AN XY:

727154

show subpopulations

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.:

Cov.:

AF XY:

0.00488

AC XY:

363

AN XY:

74454

show subpopulations

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.:

Bravo

AF:

0.00519

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00539

AC:

655

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00742

EpiControl

AF:

0.00800

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SKIC3: BP4, BS2 -
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	Labcorp Genetics (formerly Invitae), Labcorp	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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2023	- -

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

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0046

T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

.;T

MetaRNN

Benign

0.0079

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.5

L;L

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

.;N

REVEL

Benign

0.22

Sift

Benign

0.31

.;T

Sift4G

Benign

0.12

.;T

Polyphen

0.13

B;B

Vest4

0.21

MVP

0.71

MPC

0.10

ClinPred

0.0074

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over