rs1135401778

Positions:

• chr17-67854314-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_182641.4(BPTF):​c.989del​(p.Leu330ArgfsTer28) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BPTF NM_182641.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.27

Genes affected

BPTF (HGNC:3581): (bromodomain PHD finger transcription factor) This gene was identified by the reactivity of its encoded protein to a monoclonal antibody prepared against brain homogenates from patients with Alzheimer's disease. Analysis of the original protein (fetal Alz-50 reactive clone 1, or FAC1), identified as an 810 aa protein containing a DNA-binding domain and a zinc finger motif, suggested it might play a role in the regulation of transcription. High levels of FAC1 were detected in fetal brain and in patients with neurodegenerative diseases. The protein encoded by this gene is actually much larger than originally thought, and it also contains a C-terminal bromodomain characteristic of proteins that regulate transcription during proliferation. The encoded protein is highly similar to the largest subunit of the Drosophila NURF (nucleosome remodeling factor) complex. In Drosophila, the NURF complex, which catalyzes nucleosome sliding on DNA and interacts with sequence-specific transcription factors, is necessary for the chromatin remodeling required for transcription. Two alternative transcripts encoding different isoforms have been described completely. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-67854314-CT-C is Pathogenic according to our data. Variant chr17-67854314-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 431072.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-67854314-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BPTF	NM_182641.4	c.989del	p.Leu330ArgfsTer28	frameshift_variant	2/28	ENST00000306378.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BPTF	ENST00000306378.11	c.989del	p.Leu330ArgfsTer28	frameshift_variant	2/28	1	NM_182641.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Secondary microcephaly;C0454641:Expressive language delay;C0557874:Global developmental delay Pathogenic:1

Pathogenic, no assertion criteria provided

research

Baylor Genetics

Jul 03, 2017

This frameshift variant was found de novo in a 7-year-old male with moderate intellectual disability, aggression, disturbed sleep, hypotonia, postnatal microcephaly, dysmorphic features, cataract, cryptorchidism, ataxia. -

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 07, 2017

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Aug 01, 2017

De novo LOF variant in BPTF identified in a male patient with IQ 54, mild short stature, microcephaly, sleeping difficulties, sometimes aggressivity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1135401778; hg19: chr17-65850430;