17-67825768-CCGCTGCGGAG-C

Position:

• chr17-67825768-CCGCTGCGGAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_182641.4(BPTF):​c.52_61delGAGCGCTGCG​(p.Glu18fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: BPTF NM_182641.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.24

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-67825768-CCGCTGCGGAG-C is Pathogenic according to our data. Variant chr17-67825768-CCGCTGCGGAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 976787.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPTF	NM_182641.4	c.52_61delGAGCGCTGCG	p.Glu18fs	frameshift_variant	1/28	ENST00000306378.11	NP_872579.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BPTF	ENST00000306378.11	c.52_61delGAGCGCTGCG	p.Glu18fs	frameshift_variant	1/28	1	NM_182641.4	ENSP00000307208.6
BPTF	ENST00000582467.2	c.52_61delGAGCGCTGCG	p.Glu18fs	frameshift_variant	1/32	5		ENSP00000463776.2
BPTF	ENST00000321892.8	c.52_61delGAGCGCTGCG	p.Glu18fs	frameshift_variant	1/30	5		ENSP00000315454.4
BPTF	ENST00000544778.6	c.52_61delGAGCGCTGCG	p.Glu18fs	frameshift_variant	1/22	5		ENSP00000440854.2

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genomics Laboratory, Stanford Medicine

Mar 19, 2020

The p.Glu18Profs*44 variant in the BPTF gene was identified de novo in this individual, but has not been previously reported in association with disease. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). However, the ability to detect this type of variation may be limited. The p.Glu18Profs*44 variant results in a 10 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 44 amino acids downstream. The premature termination codon is in exon 1 of 28 coding exons, and is therefore predicted to undergo nonsense-mediated decay resulting in a truncated or absent protein. Heterozygous loss of function is an established mechanism of disease for the BPTF gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Glu18Profs*44 variant as pathogenic for autosomal dominant BPTFassociated neurodevelopmental disorder based on the information above. [ACMG evidence codes used: PVS1; PM2; PS2_Supporting] -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2055932118; hg19: chr17-65821884;