16-30989353-AG-AGG

Variant names:

• chr16-30989353-A-AG
• rs961318568
• NM_052874.5:c.*3467dupC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_052874.5(STX1B):​c.*3467dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 149,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STX1B NM_052874.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.450
• Publications: 0 publications found

Genes affected

STX1B (HGNC:18539): (syntaxin 1B) The protein encoded by this gene belongs to a family of proteins thought to play a role in the exocytosis of synaptic vesicles. Vesicle exocytosis releases vesicular contents and is important to various cellular functions. For instance, the secretion of transmitters from neurons plays an important role in synaptic transmission. After exocytosis, the membrane and proteins from the vesicle are retrieved from the plasma membrane through the process of endocytosis. Mutations in this gene have been identified as one cause of fever-associated epilepsy syndromes. A possible link between this gene and Parkinson's disease has also been suggested. [provided by RefSeq, Jan 2015]

HSD3B7 (HGNC:18324): (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7) This gene encodes an enzyme which is involved in the initial stages of the synthesis of bile acids from cholesterol and a member of the short-chain dehydrogenase/reductase superfamily. The encoded protein is a membrane-associated endoplasmic reticulum protein which is active against 7-alpha hydrosylated sterol substrates. Mutations in this gene are associated with a congenital bile acid synthesis defect which leads to neonatal cholestasis, a form of progressive liver disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

HSD3B7 Gene-Disease associations (from GenCC):

• congenital bile acid synthesis defect 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 232 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052874.5. 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
	STX1B	NM_052874.5	MANE Select	c.*3467dupC		3_prime_UTR	Exon 10 of 10	NP_443106.1	P61266-1
	HSD3B7	NM_025193.4	MANE Select	c.*1170_*1171insG		downstream_gene	N/A	NP_079469.2
	HSD3B7	NM_001142777.2		c.*1526_*1527insG		downstream_gene	N/A	NP_001136249.1	Q9H2F3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX1B	ENST00000215095.11	TSL:1 MANE Select	c.*3467dupC		3_prime_UTR	Exon 10 of 10	ENSP00000215095.5	P61266-1
	STX1B	ENST00000916717.1		c.*3467dupC		3_prime_UTR	Exon 10 of 10	ENSP00000586776.1
	HSD3B7	ENST00000297679.10	TSL:1 MANE Select	c.*1170_*1171insG		downstream_gene	N/A	ENSP00000297679.5	Q9H2F3-1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 232 AN: 149576 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000399

Gnomad ASJ AF: 0.0108

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.00255

Gnomad FIN AF: 0.0000970

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.00198

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 60 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 38

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 44

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.00155 AC: 232 AN: 149694 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 98 AN XY: 73064

African (AFR) AF: 0.000564 AC: 23 AN: 40812

American (AMR) AF: 0.000399 AC: 6 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 37 AN: 3436

East Asian (EAS) AF: 0.000200 AC: 1 AN: 5010

South Asian (SAS) AF: 0.00255 AC: 12 AN: 4704

European-Finnish (FIN) AF: 0.0000970 AC: 1 AN: 10310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00220 AC: 148 AN: 67136

Other (OTH) AF: 0.00196 AC: 4 AN: 2042

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neonatal hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
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: rs961318568; hg19: chr16-31000674;