17-67903834-CAA-CAAA

Variant names:

• chr17-67903834-C-CA
• rs753044214
• NM_182641.4:c.2598dupA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_182641.4(BPTF):​c.2598dupA​(p.Glu867ArgfsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,540,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: BPTF NM_182641.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.22

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-67903834-C-CA is Pathogenic according to our data. Variant chr17-67903834-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520550.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.
• BS2: High AC in GnomAdExome4 at 244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BPTF	NM_182641.4	c.2598dupA	p.Glu867ArgfsTer23	frameshift_variant	Exon 8 of 28	ENST00000306378.11	NP_872579.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BPTF	ENST00000306378.11	c.2598dupA	p.Glu867ArgfsTer23	frameshift_variant	Exon 8 of 28	1	NM_182641.4	ENSP00000307208.6

Frequencies

GnomAD3 genomes AF: 0.00000679 AC: 1 AN: 147212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000175 AC: 244 AN: 1392822 Hom.: 0 Cov.: 29 AF XY: 0.000170 AC XY: 118 AN XY: 692590

Gnomad4 AFR exome AF: 0.000296

Gnomad4 AMR exome AF: 0.000737

Gnomad4 ASJ exome AF: 0.000121

Gnomad4 EAS exome AF: 0.000214

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.0000775

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.000314

GnomAD4 genome AF: 0.00000679 AC: 1 AN: 147212 Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1 AN XY: 71516

Gnomad4 AFR AF: 0.0000251

Gnomad4 AMR AF: 0.00

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 13, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as de novo in an individual with multiple congenital anomalies in a study on candidate genes, however, specific clinical information was not provided (Farwell Hagman et al., 2017); please note this variant is referred to as E867Rfs*23 using alternate nomenclature; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27513193, 26899553) -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs753044214; hg19: chr17-65899950;