9-127695053-TTGATGATGATGATGATGATGATGATGATGA-TTGATGATGATGATGATGATGATGATGATGATGATGATGA

Variant names:

• chr9-127695053-T-TTGATGATGA
• rs57076743
• ENST00000335223.5:c.285_293dupTCATCATCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The ENST00000335223.5(PTRH1):​c.285_293dupTCATCATCA​(p.His95_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 0.014 (19 hom., cov: 0)
  • Exomes 𝑓: 0.015 (34 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
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0146 (7673/524034) while in subpopulation SAS AF = 0.0203 (1200/59124). AF 95% confidence interval is 0.0193. There are 34 homozygotes in GnomAdExome4. There are 4253 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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.*70_*78dupATGATGATG		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.285_293dupTCATCATCA	p.His95_His97dup	disruptive_inframe_insertion	Exon 2 of 3	ENSP00000493136.1	A0A286YF52
	STXBP1	ENST00000636962.2	TSL:5	c.*70_*78dupATGATGATG		3_prime_UTR	Exon 19 of 19	ENSP00000489762.1	A0A1B0GWF2
	STXBP1	ENST00000635950.2	TSL:5	n.*70_*78dupATGATGATG		non_coding_transcript_exon	Exon 19 of 20	ENSP00000490903.1	A0A1B0GWF2

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2051 AN: 147578 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00776

Gnomad ASJ AF: 0.00610

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.0171

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.0129 AC: 1510 AN: 117166 AF XY: 0.0128

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.00745

Gnomad ASJ exome AF: 0.00541

Gnomad EAS exome AF: 0.0199

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0146 AC: 7673 AN: 524034 Hom.: 34 Cov.: 0 AF XY: 0.0150 AC XY: 4253 AN XY: 283506

African (AFR) AF: 0.0114 AC: 170 AN: 14962

American (AMR) AF: 0.00995 AC: 326 AN: 32752

Ashkenazi Jewish (ASJ) AF: 0.00736 AC: 139 AN: 18874

East Asian (EAS) AF: 0.0140 AC: 444 AN: 31682

South Asian (SAS) AF: 0.0203 AC: 1200 AN: 59124

European-Finnish (FIN) AF: 0.0159 AC: 499 AN: 31420

Middle Eastern (MID) AF: 0.0105 AC: 41 AN: 3896

European-Non Finnish (NFE) AF: 0.0148 AC: 4466 AN: 302158

Other (OTH) AF: 0.0133 AC: 388 AN: 29166

GnomAD4 genome AF: 0.0139 AC: 2051 AN: 147698 Hom.: 19 Cov.: 0 AF XY: 0.0137 AC XY: 982 AN XY: 71766

African (AFR) AF: 0.0138 AC: 552 AN: 39972

American (AMR) AF: 0.00768 AC: 113 AN: 14716

Ashkenazi Jewish (ASJ) AF: 0.00610 AC: 21 AN: 3444

East Asian (EAS) AF: 0.0159 AC: 79 AN: 4980

South Asian (SAS) AF: 0.0171 AC: 77 AN: 4510

European-Finnish (FIN) AF: 0.0128 AC: 127 AN: 9920

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.0156 AC: 1047 AN: 66930

Other (OTH) AF: 0.0162 AC: 33 AN: 2038

Alfa AF: 0.0100 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;