17-67825802-A-ACCGCCG

Position:

• chr17-67825802-A-ACCGCCG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_182641.4(BPTF):​c.87_92dupGCCGCC​(p.Pro30_Pro31dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000778 in 1,027,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: BPTF NM_182641.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.44

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_benign. Variant got -5 ACMG points.

• BP6: Variant 17-67825802-A-ACCGCCG is Benign according to our data. Variant chr17-67825802-A-ACCGCCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1971703.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPTF	NM_182641.4	c.87_92dupGCCGCC	p.Pro30_Pro31dup	disruptive_inframe_insertion	1/28	ENST00000306378.11	NP_872579.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BPTF	ENST00000306378.11	c.87_92dupGCCGCC	p.Pro30_Pro31dup	disruptive_inframe_insertion	1/28	1	NM_182641.4	ENSP00000307208.6
BPTF	ENST00000582467.2	c.87_92dupGCCGCC	p.Pro30_Pro31dup	disruptive_inframe_insertion	1/32	5		ENSP00000463776.2
BPTF	ENST00000321892.8	c.87_92dupGCCGCC	p.Pro30_Pro31dup	disruptive_inframe_insertion	1/30	5		ENSP00000315454.4
BPTF	ENST00000544778.6	c.87_92dupGCCGCC	p.Pro30_Pro31dup	disruptive_inframe_insertion	1/22	5		ENSP00000440854.2

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146174 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000677

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000681 AC: 6 AN: 881490 Hom.: 0 Cov.: 31 AF XY: 0.00000729 AC XY: 3 AN XY: 411572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000378

Gnomad4 OTH exome AF: 0.0000992

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146174 Hom.: 0 Cov.: 30 AF XY: 0.0000141 AC XY: 1 AN XY: 71130

Gnomad4 AFR AF: 0.0000247

Gnomad4 AMR AF: 0.0000677

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with BPTF-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant, c.87_92dup, results in the insertion of 2 amino acid(s) of the BPTF protein (p.Pro30_Pro31dup), but otherwise preserves the integrity of the reading frame. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	BPTF: BP3 -

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: rs1489258620; hg19: chr17-65821918;