17-67903834-CAA-CAAA

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

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. 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. 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
• 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 9 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 VariationId is 520550.

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.2598dupA	p.Glu867ArgfsTer23	frameshift	Exon 8 of 28	NP_872579.2
	BPTF	NM_001439139.1		c.2787dupA	p.Glu930ArgfsTer23	frameshift	Exon 9 of 29	NP_001426068.1
	BPTF	NM_001439140.1		c.2976dupA	p.Glu993ArgfsTer23	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.2598dupA	p.Glu867ArgfsTer23	frameshift	Exon 8 of 28	ENSP00000307208.6	Q12830-2
	BPTF	ENST00000342579.8	TSL:1	c.2667dupA	p.Glu890fs	frameshift	Exon 10 of 31	ENSP00000343837.5	E9PE19
	BPTF	ENST00000424123.7	TSL:1	c.2559dupA	p.Glu854ArgfsTer23	frameshift	Exon 10 of 30	ENSP00000388405.3	E7ETD6

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

GnomAD2 exomes AF: 0.000473 AC: 86 AN: 181974 AF XY: 0.000411

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00112

Gnomad ASJ exome AF: 0.000259

Gnomad EAS exome AF: 0.000593

Gnomad FIN exome AF: 0.0000508

Gnomad NFE exome AF: 0.000366

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000175 AC: 244 AN: 1392822 Hom.: 0 Cov.: 29 AF XY: 0.000170 AC XY: 118 AN XY: 692590

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

African (AFR) AF: 0.000296 AC: 9 AN: 30384

American (AMR) AF: 0.000737 AC: 27 AN: 36658

Ashkenazi Jewish (ASJ) AF: 0.000121 AC: 3 AN: 24764

East Asian (EAS) AF: 0.000214 AC: 8 AN: 37392

South Asian (SAS) AF: 0.000417 AC: 32 AN: 76808

European-Finnish (FIN) AF: 0.0000775 AC: 4 AN: 51612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 0.000133 AC: 143 AN: 1072340

Other (OTH) AF: 0.000314 AC: 18 AN: 57320

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

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

African (AFR) AF: 0.0000251 AC: 1 AN: 39904

American (AMR) AF: 0.00 AC: 0 AN: 14754

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: 0.00 AC: 0 AN: 9494

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66650

Other (OTH) AF: 0.00 AC: 0 AN: 2006

⚠️ 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: 0.000484 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

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: COSV58844102;