rs1555649483

Positions:

• chr17-67909750-AGAAGGACCAAGG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_182641.4(BPTF):​c.2982_2992+1delGAAGGACCAAGG​(p.Lys995fs) variant causes a frameshift, splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BPTF NM_182641.4 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.88

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 11 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 17-67909750-AGAAGGACCAAGG-A is Pathogenic according to our data. Variant chr17-67909750-AGAAGGACCAAGG-A is described in ClinVar as [Pathogenic]. Clinvar id is 431069.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-67909750-AGAAGGACCAAGG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPTF	NM_182641.4	c.2982_2992+1delGAAGGACCAAGG	p.Lys995fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	10/28	ENST00000306378.11	NP_872579.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BPTF	ENST00000306378.11	c.2982_2992+1delGAAGGACCAAGG	p.Lys995fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	10/28	1	NM_182641.4	ENSP00000307208.6

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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/splicing variant was found de novo in a 13-year-old male with postnatal microcephaly, language delay, autistic features, dysmorphic features. -

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: rs1555649483; hg19: chr17-65905866;