NM_014639.4:c.3808C>G

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.3808C>G(p.Pro1270Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,613,796 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 3 hom. )

Consequence

SKIC3
NM_014639.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 8.02

Publications

5 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=0.013451397).

BP6

Variant 5-95491031-G-C is Benign according to our data. Variant chr5-95491031-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430077.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000269 (41/152140) while in subpopulation SAS AF = 0.0027 (13/4818). AF 95% confidence interval is 0.0016. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC3	NM_014639.4 link	c.3808C>G	p.Pro1270Ala	missense_variant	Exon 37 of 43	ENST00000358746.7	NP_055454.1	Q6PGP7
SKIC3	XM_047417937.1 link	c.3808C>G	p.Pro1270Ala	missense_variant	Exon 37 of 43		XP_047273893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC3	ENST00000358746.7 link	c.3808C>G	p.Pro1270Ala	missense_variant	Exon 37 of 43	1	NM_014639.4	ENSP00000351596.3		Q6PGP7

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000622

AC:

156

AN:

250826

AF XY:

0.000730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000447

AC:

653

AN:

1461656

Hom.:

Cov.:

AF XY:

0.000513

AC XY:

373

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.000358

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00301

AC:

260

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000285

AC:

317

AN:

1111914

Other (OTH)

AF:

0.000596

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000269

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0000964

AC:

AN:

41502

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00270

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000309

Hom.:

Bravo

AF:

0.000215

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000700

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23302111, 34426522, 29868001, 29527791, 21120949, 27035375, 37384835) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SKIC3: BP4, BS2 -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Trichohepatoenteric syndrome 1

Uncertain:3

Jul 21, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 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 37 p.Pro1270Ala (c.3808C>G): This variant has been reported in the literature in at least 2 individuals with trichohepatoenteric syndrome (Fabre 2011 PMID:21120949, Busoni 2017 PMID:28027214, Vely 2018 PMID:29868001). This variant is present in 0.02% (19/68016) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-95491031-G-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:430077). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

.;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

8.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.7

.;N

REVEL

Benign

0.28

Sift

Benign

0.14

.;T

Sift4G

Benign

0.15

.;T

Polyphen

0.85

P;P

Vest4

0.87

MVP

0.47

MPC

0.43

ClinPred

0.083

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.37

Mutation Taster

=61/39

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