dbSNP rs746874042: SKIC3:c.2578-7_2578-3delTTTTT (chr5-95516411-TAAAAA-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_014639.4(SKIC3):c.2578-7_2578-3delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,612,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SKIC3
NM_014639.4 splice_region, intron

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.02

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-95516411-TAAAAA-T is Pathogenic according to our data. Variant chr5-95516411-TAAAAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SKIC3	NM_014639.4 link	c.2578-7_2578-3delTTTTT	splice_region_variant, intron_variant	Intron 24 of 42	ENST00000358746.7	NP_055454.1	Q6PGP7
SKIC3	XM_047417937.1 link	c.2578-7_2578-3delTTTTT	splice_region_variant, intron_variant	Intron 24 of 42		XP_047273893.1
SKIC3	XM_047417938.1 link	c.2578-7_2578-3delTTTTT	splice_region_variant, intron_variant	Intron 24 of 28		XP_047273894.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC3	ENST00000358746.7 link	c.2578-7_2578-3delTTTTT		splice_region_variant, intron_variant	Intron 24 of 42	1	NM_014639.4	ENSP00000351596.3		Q6PGP7

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

250310

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000146

AC:

213

AN:

1460836

Hom.:

AF XY:

0.000142

AC XY:

103

AN XY:

726746

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000982

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Oct 01, 2018

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 24 of the TTC37 gene. It does not directly change the encoded amino acid sequence of the TTC37 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs746874042, gnomAD 0.009%). This variant has been observed in individuals with trichohepatoenteric syndrome (PMID: 21120949, 35599849). This variant is also known as c.2577-7_-3delTTTTT (p.Asn860_878GluDel). ClinVar contains an entry for this variant (Variation ID: 31236). Studies have shown that this variant results in skipping of exon 25, but is expected to preserve the integrity of the reading-frame (PMID: 21120949). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Trichohepatoenteric syndrome 1

Pathogenic:2

Dec 08, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TTC37 c.2578-7_2578-3delTTTTT variant (rs746874042) is reported in the literature in the compound heterozygous state with another TTC37 variant in at least one individual affected with trichohepatoenteric syndrome-1 (reported as c.2577-7_-3delTTTTT, Fabre 2011). This variant is reported in ClinVar (Variation ID: 31236), and is found in the non-Finnish European population with an allele frequency of 0.012% (15/128584 alleles) in the Genome Aggregation Database. This is an intronic variant that deletes five nucleotides, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by disrupting the canonical splice acceptor site of intron 24, which is likely to negatively impact gene function. Analysis of patient RNA shows that this variant leads to skipping of exon 25, and the deletion of 19 in-frame amino acids. Based on available information, this variant is considered to be likely pathogenic. References: Fabre A et al. Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome. Hum Mutat. 2011 Mar;32(3):277-81. -

Mar 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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