17-67903834-CAA-CA

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_182641.4(BPTF):​c.2598delA​(p.Glu867ArgfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,537,806 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: BPTF NM_182641.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.22
• Publications: 5 publications found

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]

BPTF Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• neurodevelopmental disorder with dysmorphic facies and distal limb anomalies

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182641.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPTF	NM_182641.4	MANE Select	c.2598delA	p.Glu867ArgfsTer16	frameshift	Exon 8 of 28	NP_872579.2
	BPTF	NM_001439139.1		c.2787delA	p.Glu930ArgfsTer16	frameshift	Exon 9 of 29	NP_001426068.1
	BPTF	NM_001439140.1		c.2976delA	p.Glu993ArgfsTer16	frameshift	Exon 10 of 31	NP_001426069.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPTF	ENST00000306378.11	TSL:1 MANE Select	c.2598delA	p.Glu867ArgfsTer16	frameshift	Exon 8 of 28	ENSP00000307208.6	Q12830-2
	BPTF	ENST00000342579.8	TSL:1	c.2667delA	p.Glu890fs	frameshift	Exon 10 of 31	ENSP00000343837.5	E9PE19
	BPTF	ENST00000424123.7	TSL:1	c.2559delA	p.Glu854ArgfsTer16	frameshift	Exon 10 of 30	ENSP00000388405.3	E7ETD6

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000211

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00171 AC: 312 AN: 181974 AF XY: 0.00158

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.00462

Gnomad ASJ exome AF: 0.00155

Gnomad EAS exome AF: 0.00169

Gnomad FIN exome AF: 0.000406

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00169

GnomAD4 exome AF: 0.000380 AC: 528 AN: 1390608 Hom.: 0 Cov.: 29 AF XY: 0.000398 AC XY: 275 AN XY: 691378

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000594 AC: 18 AN: 30310

American (AMR) AF: 0.00242 AC: 88 AN: 36388

Ashkenazi Jewish (ASJ) AF: 0.000567 AC: 14 AN: 24686

East Asian (EAS) AF: 0.000429 AC: 16 AN: 37322

South Asian (SAS) AF: 0.00139 AC: 106 AN: 76520

European-Finnish (FIN) AF: 0.000252 AC: 13 AN: 51498

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5542

European-Non Finnish (NFE) AF: 0.000226 AC: 242 AN: 1071130

Other (OTH) AF: 0.000524 AC: 30 AN: 57212

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147198 Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1 AN XY: 71504

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 39906

American (AMR) AF: 0.00 AC: 0 AN: 14752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4680

European-Finnish (FIN) AF: 0.000211 AC: 2 AN: 9484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66644

Other (OTH) AF: 0.00 AC: 0 AN: 2008

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00149 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=1/199	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs753044214; hg19: chr17-65899950; COSMIC: COSV58830797;