ENST00000335223.5:c.285_293delTCATCATCA

Variant names:

• chr9-127695053-TTGATGATGA-T
• rs57076743
• ENST00000335223.5:c.285_293delTCATCATCA

Variant summary

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

The ENST00000335223.5(PTRH1):​c.285_293delTCATCATCA​(p.His95_His97del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0347 in 671,758 control chromosomes in the GnomAD database, including 366 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.033 (90 hom., cov: 0)
  • Exomes 𝑓: 0.035 (276 hom.)
• Consequence: PTRH1 ENST00000335223.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• 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 nfe. GnomAd4 allele frequency = 0.033 (4879/147708) while in subpopulation NFE AF = 0.0421 (2820/66938). AF 95% confidence interval is 0.0408. There are 90 homozygotes in GnomAd4. There are 2370 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 90 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_*78delATGATGATG		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_293delTCATCATCA	p.His95_His97del	disruptive_inframe_deletion	Exon 2 of 3	ENSP00000493136.1	A0A286YF52
	STXBP1	ENST00000636962.2	TSL:5	c.*70_*78delATGATGATG		3_prime_UTR	Exon 19 of 19	ENSP00000489762.1	A0A1B0GWF2
	STXBP1	ENST00000635950.2	TSL:5	n.*70_*78delATGATGATG		non_coding_transcript_exon	Exon 19 of 20	ENSP00000490903.1	A0A1B0GWF2

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 4878 AN: 147588 Hom.: 90 Cov.: 0

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0189

Gnomad EAS AF: 0.00441

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.0422

Gnomad OTH AF: 0.0338

GnomAD2 exomes AF: 0.0329 AC: 3850 AN: 117166 AF XY: 0.0337

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.0317

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.00317

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0431

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0352 AC: 18461 AN: 524050 Hom.: 276 AF XY: 0.0354 AC XY: 10043 AN XY: 283516

African (AFR) AF: 0.0214 AC: 320 AN: 14964

American (AMR) AF: 0.0311 AC: 1018 AN: 32758

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 466 AN: 18876

East Asian (EAS) AF: 0.00221 AC: 70 AN: 31680

South Asian (SAS) AF: 0.0292 AC: 1728 AN: 59128

European-Finnish (FIN) AF: 0.0314 AC: 988 AN: 31424

Middle Eastern (MID) AF: 0.0151 AC: 59 AN: 3896

European-Non Finnish (NFE) AF: 0.0426 AC: 12858 AN: 302150

Other (OTH) AF: 0.0327 AC: 954 AN: 29174

GnomAD4 genome AF: 0.0330 AC: 4879 AN: 147708 Hom.: 90 Cov.: 0 AF XY: 0.0330 AC XY: 2370 AN XY: 71778

African (AFR) AF: 0.0204 AC: 816 AN: 39968

American (AMR) AF: 0.0398 AC: 586 AN: 14718

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 65 AN: 3446

East Asian (EAS) AF: 0.00442 AC: 22 AN: 4980

South Asian (SAS) AF: 0.0330 AC: 149 AN: 4510

European-Finnish (FIN) AF: 0.0245 AC: 243 AN: 9922

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

European-Non Finnish (NFE) AF: 0.0421 AC: 2820 AN: 66938

Other (OTH) AF: 0.0334 AC: 68 AN: 2038

Alfa AF: 0.0335 Hom.: 1157

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

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;