9-127695053-TTGATGATGATGATGATGATGATGATGATGA-TTGATGATGATGATGATGATGATGATGATGATGATGA

Variant names:

• chr9-127695053-T-TTGATGA
• rs57076743
• ENST00000335223.5:c.288_293dupTCATCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BA1

The ENST00000335223.5(PTRH1):​c.288_293dupTCATCA​(p.His96_His97dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.084 (588 hom., cov: 0)
  • Exomes 𝑓: 0.076 (761 hom.)
• Consequence: PTRH1 ENST00000335223.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.463
• Publications: 0 publications found

Genes affected

PTRH1 (HGNC:27039): (peptidyl-tRNA hydrolase 1 homolog) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000335223.5
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000335223.5. 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
	STXBP1	NM_001374314.1		c.*73_*78dupATGATG		3_prime_UTR	Exon 19 of 19	NP_001361243.1	A0A1B0GWF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTRH1	ENST00000335223.5	TSL:1	c.288_293dupTCATCA	p.His96_His97dup	disruptive_inframe_insertion	Exon 2 of 3	ENSP00000493136.1	A0A286YF52
	STXBP1	ENST00000636962.2	TSL:5	c.*73_*78dupATGATG		3_prime_UTR	Exon 19 of 19	ENSP00000489762.1	A0A1B0GWF2
	STXBP1	ENST00000635950.2	TSL:5	n.*73_*78dupATGATG		non_coding_transcript_exon	Exon 19 of 20	ENSP00000490903.1	A0A1B0GWF2

Frequencies

GnomAD3 genomes AF: 0.0837 AC: 12344 AN: 147494 Hom.: 587 Cov.: 0

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00667

Gnomad AMR AF: 0.0731

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0852

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0638

Gnomad MID AF: 0.0784

Gnomad NFE AF: 0.0648

Gnomad OTH AF: 0.0820

GnomAD2 exomes AF: 0.0746 AC: 8741 AN: 117166 AF XY: 0.0746

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0759

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.0910

Gnomad FIN exome AF: 0.0593

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0709

GnomAD4 exome AF: 0.0759 AC: 39714 AN: 523304 Hom.: 761 Cov.: 0 AF XY: 0.0784 AC XY: 22196 AN XY: 283070

African (AFR) AF: 0.125 AC: 1872 AN: 14942

American (AMR) AF: 0.0808 AC: 2640 AN: 32676

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 859 AN: 18848

East Asian (EAS) AF: 0.0835 AC: 2643 AN: 31658

South Asian (SAS) AF: 0.124 AC: 7305 AN: 58994

European-Finnish (FIN) AF: 0.0720 AC: 2261 AN: 31392

Middle Eastern (MID) AF: 0.0599 AC: 233 AN: 3890

European-Non Finnish (NFE) AF: 0.0653 AC: 19700 AN: 301766

Other (OTH) AF: 0.0755 AC: 2201 AN: 29138

GnomAD4 genome AF: 0.0837 AC: 12361 AN: 147614 Hom.: 588 Cov.: 0 AF XY: 0.0852 AC XY: 6113 AN XY: 71710

African (AFR) AF: 0.123 AC: 4917 AN: 39932

American (AMR) AF: 0.0731 AC: 1075 AN: 14710

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 159 AN: 3446

East Asian (EAS) AF: 0.0854 AC: 425 AN: 4976

South Asian (SAS) AF: 0.137 AC: 614 AN: 4498

European-Finnish (FIN) AF: 0.0638 AC: 633 AN: 9918

Middle Eastern (MID) AF: 0.0734 AC: 21 AN: 286

European-Non Finnish (NFE) AF: 0.0648 AC: 4338 AN: 66910

Other (OTH) AF: 0.0849 AC: 173 AN: 2038

Alfa AF: 0.0608 Hom.: 1157

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46

Splicing

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

Other links and lift over

dbSNP: rs57076743; hg19: chr9-130457332;