1-231337272-C-CT

Variant names:

• chr1-231337272-C-CT
• NM_175876.5:c.473dupA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_175876.5(EXOC8):​c.473dupA​(p.Gln159AlafsTer9) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXOC8 NM_175876.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.82

Genes affected

EXOC8 (HGNC:24659): (exocyst complex component 8) This gene encodes a component of the exocyst complex, an evolutionarily conserved multi-protein complex that plays a critical role in vesicular trafficking and the secretory pathway by targeting post-Golgi vesicles to the plasma membrane. This protein is a target of activated Ral subfamily of GTPases and thereby regulates exocytosis by tethering vesicles to the plasma membrane. Mutations in this gene may be related to Joubert syndrome. [provided by RefSeq, Sep 2016]

SPRTN (HGNC:25356): (SprT-like N-terminal domain) The protein encoded by this gene may play a role in DNA repair during replication of damaged DNA. This protein recruits valosin containing protein (p97) to stalled DNA replication forks where it may prevent excessive translesional DNA synthesis and limit the number of DNA-damage induced mutations. It may also be involved in replication-related G2/M-checkpoint regulation. Deficiency of a similar protein in mouse causes chromosomal instability and progeroid phenotypes. Mutations in this gene have been associated with Ruijs-Aalfs syndrome (RJALS). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-231337272-C-CT is Pathogenic according to our data. Variant chr1-231337272-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3769535.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC8	NM_175876.5	c.473dupA	p.Gln159AlafsTer9	frameshift_variant	Exon 1 of 1	ENST00000366645.1	NP_787072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC8	ENST00000366645.1	c.473dupA	p.Gln159AlafsTer9	frameshift_variant	Exon 1 of 1	6	NM_175876.5	ENSP00000355605.2
SPRTN	ENST00000391858	c.-1109dupT		5_prime_UTR_variant	Exon 1 of 4	1		ENSP00000375731.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy Pathogenic:1

Jan 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EXOC8 c.473dupA (p.Gln159AlafsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein. The variant was absent in 245150 control chromosomes (gnomAD). To our knowledge, no occurrence of c.473dupA in individuals affected with neurodevelopmental disorder with microcephaly, seizures, and brain atrophy and no experimental evidence demonstrating its impact on protein function have been reported. Two downstream truncations (example: p.E572*, pAsp607*) have been reported in the literature in homozygous individuals affected with brain atrophy, seizures, developmental delay and microcephaly (PMID: 35460391, 32103185) where the variant segregated with the disease in two large families. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-231473018;