rs886041028

Variant names:

• chr6-107908926-C-T
• rs886041028
• NM_007214.5:c.733+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1 PM2 PP5_Very_Strong BS2_Supporting

The NM_007214.5(SEC63):​c.733+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,411,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SEC63 NM_007214.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.53

Genes affected

SEC63 (HGNC:21082): (SEC63 homolog, protein translocation regulator) The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein encoded by this gene and SEC62 protein are found to be associated with ribosome-free SEC61 complex. It is speculated that Sec61-Sec62-Sec63 may perform post-translational protein translocation into the ER. The Sec61-Sec62-Sec63 complex might also perform the backward transport of ER proteins that are subject to the ubiquitin-proteasome-dependent degradation pathway. The encoded protein is an integral membrane protein located in the rough ER. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-107908926-C-T is Pathogenic according to our data. Variant chr6-107908926-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC63	NM_007214.5	c.733+1G>A		splice_donor_variant, intron_variant	Intron 8 of 20	ENST00000369002.9	NP_009145.1
SEC63	XM_047418130.1	c.565+1G>A		splice_donor_variant, intron_variant	Intron 8 of 20		XP_047274086.1
SEC63	XM_047418131.1	c.313+1G>A		splice_donor_variant, intron_variant	Intron 7 of 19		XP_047274087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC63	ENST00000369002.9	c.733+1G>A		splice_donor_variant, intron_variant	Intron 8 of 20	1	NM_007214.5	ENSP00000357998.4
SEC63	ENST00000489455.1	n.233+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	5
SEC63	ENST00000429168.1	c.*82G>A		downstream_gene_variant		5		ENSP00000403144.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249006 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134554

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1411692 Hom.: 0 Cov.: 23 AF XY: 0.00000283 AC XY: 2 AN XY: 705512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000375

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic liver disease 2 Pathogenic:3

Dec 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). Variant is in intron 8 of 20 of the SEC63 gene. (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0703 - Comparable variant (c.733+1G>T) has moderate previous evidence for pathogenicity in a patient with polycystic liver disease (PMID: 20095989). (P) 0803 - Low previous evidence of pathogenicity in a single family with polycystic liver disease (ClinVar, PMID:15133510). (P) 0903 - Low evidence for segregation with disease in a single family (PMID:15133510) (P) 1007 - No published functional evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided Pathogenic:1

Sep 16, 2022

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the SEC63 gene demonstrated a sequence change in the canonical splice donor site of intron 8, c.733+1G>A. This sequence change has been described in the gnomAD database in a single individual corresponding to an overall frequency of 0.0004% (dbSNP rs886041028). This pathogenic sequence change has previously been described in five members of a family affected with polycystic liver disease (PMID: 15133510). Additionally, a different sequence change at this same position, c.733+1G>T, has been identified in an individual with polycystic liver disease (PMID: 20095989). Based on in-silico splice prediction programs, this sequence change likely affects normal splicing of the SEC63 gene which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively. Based on these collective evidences, this sequence change is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs886041028; hg19: chr6-108230130;