chr1-231337365-C-G

Variant names:

• chr1-231337365-C-G
• rs112630019
• NM_175876.5:c.381G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_175876.5(EXOC8):​c.381G>C​(p.Ala127Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,602,166 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (88 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (93 hom.)
• Consequence: EXOC8 NM_175876.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.276
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-231337365-C-G is Benign according to our data. Variant chr1-231337365-C-G is described in ClinVar as Benign. ClinVar VariationId is 767763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.276 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

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.381G>C	p.Ala127Ala	synonymous	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.381G>C	p.Ala127Ala	synonymous	Exon 1 of 1	ENSP00000355605.2	Q8IYI6
	SPRTN	ENST00000391858.8	TSL:1	c.-1019C>G		5_prime_UTR	Exon 1 of 4	ENSP00000375731.4	Q9H040-2

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2571 AN: 152154 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.00441 AC: 1032 AN: 233768 AF XY: 0.00337

Gnomad AFR exome AF: 0.0609

Gnomad AMR exome AF: 0.00365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.00292

GnomAD4 exome AF: 0.00186 AC: 2695 AN: 1449894 Hom.: 93 Cov.: 32 AF XY: 0.00161 AC XY: 1164 AN XY: 721716

African (AFR) AF: 0.0630 AC: 2109 AN: 33462

American (AMR) AF: 0.00392 AC: 175 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000279 AC: 24 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42408

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5754

European-Non Finnish (NFE) AF: 0.0000810 AC: 90 AN: 1111532

Other (OTH) AF: 0.00453 AC: 273 AN: 60200

GnomAD4 genome AF: 0.0170 AC: 2589 AN: 152272 Hom.: 88 Cov.: 32 AF XY: 0.0161 AC XY: 1202 AN XY: 74460

African (AFR) AF: 0.0593 AC: 2463 AN: 41546

American (AMR) AF: 0.00503 AC: 77 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68026

Other (OTH) AF: 0.0123 AC: 26 AN: 2110

Alfa AF: 0.00787 Hom.: 6

Bravo AF: 0.0193

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.69
PhyloP100		0.28
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs112630019; hg19: chr1-231473111;