9-127695053-TTGATGATGATGATGATGATGATGATGATGA-TTGATGATGATGATGATGA

Variant names:

• chr9-127695053-TTGATGATGATGA-T
• rs57076743
• ENST00000335223.5:c.282_293delTCATCATCATCA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The ENST00000335223.5(PTRH1):​c.282_293delTCATCATCATCA​(p.His94_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 0.00259 in 671,686 control chromosomes in the GnomAD database, including 6 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: PTRH1 ENST00000335223.5 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000335223.5
• BP6: Variant 9-127695053-TTGATGATGATGA-T is Benign according to our data. Variant chr9-127695053-TTGATGATGATGA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2659509.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.*67_*78delATGATGATGATG		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.282_293delTCATCATCATCA	p.His94_His97del	disruptive_inframe_deletion	Exon 2 of 3	ENSP00000493136.1	A0A286YF52
	STXBP1	ENST00000636962.2	TSL:5	c.*67_*78delATGATGATGATG		3_prime_UTR	Exon 19 of 19	ENSP00000489762.1	A0A1B0GWF2
	STXBP1	ENST00000635950.2	TSL:5	n.*67_*78delATGATGATGATG		non_coding_transcript_exon	Exon 19 of 20	ENSP00000490903.1	A0A1B0GWF2

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 354 AN: 147598 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.000443

Gnomad FIN AF: 0.00191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00189 AC: 222 AN: 117166 AF XY: 0.00185

Gnomad AFR exome AF: 0.000735

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000629

Gnomad NFE exome AF: 0.00391

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00265 AC: 1389 AN: 523968 Hom.: 6 AF XY: 0.00254 AC XY: 719 AN XY: 283484

African (AFR) AF: 0.00140 AC: 21 AN: 14966

American (AMR) AF: 0.000733 AC: 24 AN: 32754

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 3 AN: 18876

East Asian (EAS) AF: 0.0000631 AC: 2 AN: 31682

South Asian (SAS) AF: 0.000237 AC: 14 AN: 59116

European-Finnish (FIN) AF: 0.000796 AC: 25 AN: 31414

Middle Eastern (MID) AF: 0.00103 AC: 4 AN: 3896

European-Non Finnish (NFE) AF: 0.00407 AC: 1230 AN: 302098

Other (OTH) AF: 0.00226 AC: 66 AN: 29166

GnomAD4 genome AF: 0.00240 AC: 354 AN: 147718 Hom.: 0 Cov.: 0 AF XY: 0.00228 AC XY: 164 AN XY: 71782

African (AFR) AF: 0.00103 AC: 41 AN: 39974

American (AMR) AF: 0.00197 AC: 29 AN: 14718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4980

South Asian (SAS) AF: 0.000443 AC: 2 AN: 4510

European-Finnish (FIN) AF: 0.00191 AC: 19 AN: 9922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00391 AC: 262 AN: 66942

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00166 Hom.: 1157

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;