5-95482498-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

trichohepatoenteric syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
trichohepatoenteric syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SKIC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 235756.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC3	NM_014639.4 link	c.4187A>G	p.Asn1396Ser	missense_variant	Exon 39 of 43	ENST00000358746.7	NP_055454.1	Q6PGP7
SKIC3	XM_047417937.1 link	c.4187A>G	p.Asn1396Ser	missense_variant	Exon 39 of 43		XP_047273893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC3	ENST00000358746.7 link	c.4187A>G	p.Asn1396Ser	missense_variant	Exon 39 of 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

GnomAD2 exomes

AF:

0.00548

AC:

1378

AN:

251404

AF XY:

0.00580

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 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

African (AFR)

AF:

0.00146

AC:

AN:

33472

American (AMR)

AF:

0.00306

AC:

137

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00153

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39674

South Asian (SAS)

AF:

0.00666

AC:

574

AN:

86250

European-Finnish (FIN)

AF:

0.00702

AC:

375

AN:

53416

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00866

AC:

9634

AN:

1111870

Other (OTH)

AF:

0.00566

AC:

342

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

587

1174

1760

2347

2934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

366

732

1098

1464

1830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00510

AC:

777

AN:

152238

Hom.:

Cov.:

AF XY:

0.00488

AC XY:

363

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41544

American (AMR)

AF:

0.00654

AC:

100

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00435

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00678

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00718

AC:

488

AN:

67992

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00614

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

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SKIC3: BP4, BS2 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 28, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not specified

Benign:1

Dec 11, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

1.4

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

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over