chr1-231337508-G-C

Variant names:

• chr1-231337508-G-C
• rs141851139
• NM_175876.5:c.238C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_175876.5(EXOC8):​c.238C>G​(p.Leu80Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L80L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EXOC8 NM_175876.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66
• Publications: 0 publications found

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]

SPRTN Gene-Disease associations (from GenCC):

• progeroid features-hepatocellular carcinoma predisposition syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175876.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC8	NM_175876.5	MANE Select	c.238C>G	p.Leu80Val	missense	Exon 1 of 1	NP_787072.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC8	ENST00000366645.1	TSL:6 MANE Select	c.238C>G	p.Leu80Val	missense	Exon 1 of 1	ENSP00000355605.2	Q8IYI6
	SPRTN	ENST00000391858.8	TSL:1	c.-876G>C		5_prime_UTR	Exon 1 of 4	ENSP00000375731.4	Q9H040-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461342 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726992

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.059	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.7
PrimateAI	Pathogenic	0.83	D
REVEL	Pathogenic	0.66
Sift4G	Benign	0.13	T
Polyphen		0.79	P
Vest4		0.73
MutPred		0.84		Loss of disorder (P = 0.1444)
MVP		0.87
ClinPred		0.83	D
GERP RS		2.1
PromoterAI		0.11	Neutral
Varity_R		0.30
gMVP		0.84
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs141851139; hg19: chr1-231473254;