6-107868223-TAAAAA-TAAAAAA

Variant names:

• chr6-107868223-T-TA
• rs56104837
• NM_007214.5:c.*3480dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_007214.5(SEC63):​c.*3480dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: SEC63 NM_007214.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00
• Publications: 1 publications found

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]

SEC63 Gene-Disease associations (from GenCC):

• polycystic liver disease 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• polycystic liver disease 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000289 (42/145418) while in subpopulation EAS AF = 0.00597 (30/5026). AF 95% confidence interval is 0.0043. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 42 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007214.5. 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
	SEC63	NM_007214.5	MANE Select	c.*3480dupT		3_prime_UTR	Exon 21 of 21	NP_009145.1	Q9UGP8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC63	ENST00000369002.9	TSL:1 MANE Select	c.*3480dupT		3_prime_UTR	Exon 21 of 21	ENSP00000357998.4	Q9UGP8

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 42 AN: 145344 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000411

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00595

Gnomad SAS AF: 0.000216

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000452

Gnomad OTH AF: 0.000505

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.000289 AC: 42 AN: 145418 Hom.: 0 Cov.: 0 AF XY: 0.000312 AC XY: 22 AN XY: 70468

African (AFR) AF: 0.0000253 AC: 1 AN: 39520

American (AMR) AF: 0.000411 AC: 6 AN: 14608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00597 AC: 30 AN: 5026

South Asian (SAS) AF: 0.000217 AC: 1 AN: 4614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000452 AC: 3 AN: 66320

Other (OTH) AF: 0.000500 AC: 1 AN: 2002

Alfa AF: 0.00 Hom.: 2022

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Polycystic liver disease 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

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: rs56104837; hg19: chr6-108189427;