rs746874042

Variant names:

• chr5-95516411-TAAAAA-T
• rs746874042
• NM_014639.4:c.2578-7_2578-3delTTTTT

Your query was ambiguous. Multiple possible variants found:

• chr5-95516411-TAAAAA-T
• chr5-95516411-TAAAAA-TAAAA
• chr5-95516411-TAAAAA-TAAAAAA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.02
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• 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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC3	NM_014639.4	c.2578-7_2578-3delTTTTT		splice_region_variant, intron_variant	Intron 24 of 42	ENST00000358746.7	NP_055454.1
SKIC3	XM_047417937.1	c.2578-7_2578-3delTTTTT		splice_region_variant, intron_variant	Intron 24 of 42		XP_047273893.1
SKIC3	XM_047417938.1	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	c.2578-7_2578-3delTTTTT		splice_region_variant, intron_variant	Intron 24 of 42	1	NM_014639.4	ENSP00000351596.3

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152156 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000400 AC: 10 AN: 250310 AF XY: 0.0000295

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 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.: 0 AF XY: 0.000142 AC XY: 103 AN XY: 726746

African (AFR) AF: 0.0000598 AC: 2 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000177 AC: 197 AN: 1111428

Other (OTH) AF: 0.000232 AC: 14 AN: 60318

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000434 Hom.: 0

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

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

Mar 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746874042; hg19: chr5-94852115;