rs138763389

Variant names:

• chr9-127651600-T-C
• rs138763389
• NM_003165.6:c.38-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001032221.6(STXBP1):​c.38-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,388 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (27 hom., cov: 31)
  • Exomes 𝑓: 0.019 (365 hom.)
• Consequence: STXBP1 NM_001032221.6 splice_region, intron
• Scores: Splicing: ADA: 0.00004480
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.85
• Publications: 5 publications found

Genes affected

STXBP1 (HGNC:11444): (syntaxin binding protein 1) This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

STXBP1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 9-127651600-T-C is Benign according to our data. Variant chr9-127651600-T-C is described in ClinVar as Benign. ClinVar VariationId is 139343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1935/152170) while in subpopulation NFE AF = 0.0185 (1257/68008). AF 95% confidence interval is 0.0176. There are 27 homozygotes in GnomAd4. There are 954 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032221.6. 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
	STXBP1	NM_003165.6	MANE Plus Clinical	c.38-3T>C		splice_region intron	N/A	NP_003156.1	P61764-2
	STXBP1	NM_001032221.6	MANE Select	c.38-3T>C		splice_region intron	N/A	NP_001027392.1	P61764-1
	STXBP1	NM_001374306.2		c.38-3T>C		splice_region intron	N/A	NP_001361235.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP1	ENST00000373302.8	TSL:1 MANE Plus Clinical	c.38-3T>C		splice_region intron	N/A	ENSP00000362399.3	P61764-2
	STXBP1	ENST00000373299.5	TSL:1 MANE Select	c.38-3T>C		splice_region intron	N/A	ENSP00000362396.2	P61764-1
	STXBP1	ENST00000494254.4	TSL:5	c.38-3T>C		splice_region intron	N/A	ENSP00000485397.2	A0A096LP52

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1935 AN: 152052 Hom.: 27 Cov.: 31

Gnomad AFR AF: 0.00411

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0119 AC: 2997 AN: 251178 AF XY: 0.0116

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0193 AC: 28141 AN: 1461218 Hom.: 365 Cov.: 32 AF XY: 0.0184 AC XY: 13399 AN XY: 726928

African (AFR) AF: 0.00317 AC: 106 AN: 33476

American (AMR) AF: 0.00434 AC: 194 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 289 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.000615 AC: 53 AN: 86230

European-Finnish (FIN) AF: 0.0284 AC: 1515 AN: 53386

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0222 AC: 24717 AN: 1111454

Other (OTH) AF: 0.0209 AC: 1263 AN: 60374

GnomAD4 genome AF: 0.0127 AC: 1935 AN: 152170 Hom.: 27 Cov.: 31 AF XY: 0.0128 AC XY: 954 AN XY: 74386

African (AFR) AF: 0.00410 AC: 170 AN: 41504

American (AMR) AF: 0.00602 AC: 92 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0292 AC: 309 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0185 AC: 1257 AN: 68008

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.0145 Hom.: 12

Bravo AF: 0.0116

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0182

EpiControl AF: 0.0167

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.9
DANN	Benign	0.81
PhyloP100		1.8
PromoterAI		0.0099	Neutral
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0
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: rs138763389; hg19: chr9-130413879;