rs1569555

Positions:

• chr6-107921918-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007214.5(SEC63):​c.340-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0028 (2 hom.)
• Consequence: SEC63 NM_007214.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002456
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.208

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-107921918-A-G is Benign according to our data. Variant chr6-107921918-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 403427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-107921918-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0081 (25/3088) while in subpopulation NFE AF= 0.00198 (2/1010). AF 95% confidence interval is 0.000351. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEC63	NM_007214.5	c.340-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000369002.9	NP_009145.1
SEC63	XM_047418130.1	c.172-9T>C		splice_polypyrimidine_tract_variant, intron_variant			XP_047274086.1
SEC63	XM_047418131.1	c.-81-9T>C		splice_polypyrimidine_tract_variant, intron_variant			XP_047274087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEC63	ENST00000369002.9	c.340-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_007214.5	ENSP00000357998	P1
SEC63	ENST00000429168.1	c.172-9T>C		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000403144
SEC63	ENST00000484803.5	n.262-9T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00781 AC: 24 AN: 3072 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000867

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.0500

GnomAD3 exomes AF: 0.000361 AC: 63 AN: 174382 Hom.: 1 AF XY: 0.000317 AC XY: 30 AN XY: 94770

Gnomad AFR exome AF: 0.0000912

Gnomad AMR exome AF: 0.0000443

Gnomad ASJ exome AF: 0.00775

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000861

Gnomad OTH exome AF: 0.000239

GnomAD4 exome AF: 0.00282 AC: 194 AN: 68712 Hom.: 2 Cov.: 0 AF XY: 0.00280 AC XY: 95 AN XY: 33880

Gnomad4 AFR exome AF: 0.000859

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000380

Gnomad4 OTH exome AF: 0.00765

GnomAD4 genome AF: 0.00810 AC: 25 AN: 3088 Hom.: 0 Cov.: 0 AF XY: 0.00927 AC XY: 14 AN XY: 1510

Gnomad4 AFR AF: 0.00172

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.0476

Alfa AF: 0.578 Hom.: 1812

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: No change to splice consensus -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0040
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

LitVar

Other links and lift over

dbSNP: rs1569555; hg19: chr6-108243122;