17-67825816-C-T

Position:

• chr17-67825816-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_182641.4(BPTF):​c.92C>T​(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 877,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: BPTF NM_182641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.278

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 -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BPTF. . Gene score misZ 3.7096 (greater than the threshold 3.09). Trascript score misZ 5.0752 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31433073).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPTF	NM_182641.4	c.92C>T	p.Pro31Leu	missense_variant	1/28	ENST00000306378.11	NP_872579.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BPTF	ENST00000306378.11	c.92C>T	p.Pro31Leu	missense_variant	1/28	1	NM_182641.4	ENSP00000307208.6
BPTF	ENST00000582467.2	c.92C>T	p.Pro31Leu	missense_variant	1/32	5		ENSP00000463776.2
BPTF	ENST00000321892.8	c.92C>T	p.Pro31Leu	missense_variant	1/30	5		ENSP00000315454.4
BPTF	ENST00000544778.6	c.92C>T	p.Pro31Leu	missense_variant	1/22	5		ENSP00000440854.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000182 AC: 16 AN: 877098 Hom.: 0 Cov.: 31 AF XY: 0.0000147 AC XY: 6 AN XY: 409296

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: 0.0000202

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The c.92C>T (p.P31L) alteration is located in exon 1 (coding exon 1) of the BPTF gene. This alteration results from a C to T substitution at nucleotide position 92, causing the proline (P) at amino acid position 31 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.091	.;T;.
Eigen	Benign	-0.0085
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.34	.;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.77	.;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	.;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.99, 1.0	.;D;D
Vest4		0.24, 0.26
MutPred		0.24		Loss of glycosylation at P31 (P = 0.0022);Loss of glycosylation at P31 (P = 0.0022);Loss of glycosylation at P31 (P = 0.0022);
MVP		0.64
MPC		1.1
ClinPred		0.60	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.22

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: rs2055938658; hg19: chr17-65821932;