rs1555649483

Variant names:

• chr17-67909750-AGAAGGACCAAGG-A
• rs1555649483
• NM_182641.4:c.2982_2992+1delGAAGGACCAAGG

Variant summary

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

The NM_182641.4(BPTF):​c.2982_2992+1delGAAGGACCAAGG​(p.Lys995AsnfsTer1924) variant causes a frameshift, splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)

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 17-67909750-AGAAGGACCAAGG-A is Pathogenic according to our data. Variant chr17-67909750-AGAAGGACCAAGG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 431069.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPTF	NM_182641.4	MANE Select	c.2982_2992+1delGAAGGACCAAGG	p.Lys995AsnfsTer1924	frameshift splice_donor splice_region intron	Exon 10 of 28	NP_872579.2
	BPTF	NM_001439139.1		c.3171_3181+1delGAAGGACCAAGG	p.Lys1058AsnfsTer1924	frameshift splice_donor splice_region intron	Exon 11 of 29	NP_001426068.1
	BPTF	NM_001439140.1		c.3360_3370+1delGAAGGACCAAGG	p.Lys1121AsnfsTer1839	frameshift splice_donor splice_region intron	Exon 12 of 31	NP_001426069.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPTF	ENST00000306378.11	TSL:1 MANE Select	c.2982_2992+1delGAAGGACCAAGG	p.Lys995AsnfsTer1924	frameshift splice_donor splice_region intron	Exon 10 of 28	ENSP00000307208.6
	BPTF	ENST00000342579.8	TSL:1	c.3051_3061+1delGAAGGACCAAGG	p.Lys1018fs	frameshift splice_donor splice_region intron	Exon 12 of 31	ENSP00000343837.5
	BPTF	ENST00000424123.7	TSL:1	c.2943_2953+1delGAAGGACCAAGG	p.Lys982AsnfsTer1781	frameshift splice_donor splice_region intron	Exon 12 of 30	ENSP00000388405.3

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Secondary microcephaly;C0454641:Expressive language delay;C0557874:Global developmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555649483; hg19: chr17-65905866;