17-67825859-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_182641.4(BPTF):c.135C>T(p.Gly45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,013,984 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0041 (3 hom.)
• Consequence: BPTF NM_182641.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.70

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-67825859-C-T is Benign according to our data. Variant chr17-67825859-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1971132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00256 (378/147534) while in subpopulation NFE AF= 0.00313 (207/66152). AF 95% confidence interval is 0.00278. There are 0 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BPTF	NM_182641.4	c.135C>T	p.Gly45=	synonymous_variant	1/28	ENST00000306378.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BPTF	ENST00000306378.11	c.135C>T	p.Gly45=	synonymous_variant	1/28	1	NM_182641.4
BPTF	ENST00000582467.2	c.135C>T	p.Gly45=	synonymous_variant	1/32	5		P1
BPTF	ENST00000321892.8	c.135C>T	p.Gly45=	synonymous_variant	1/30	5
BPTF	ENST00000544778.6	c.135C>T	p.Gly45=	synonymous_variant	1/22	5

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 378 AN: 147426 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000337

Gnomad ASJ AF: 0.000589

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00410 AC: 3551 AN: 866450 Hom.: 3 Cov.: 31 AF XY: 0.00414 AC XY: 1670 AN XY: 403452

Gnomad4 AFR exome AF: 0.000306

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000337

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00835

Gnomad4 NFE exome AF: 0.00440

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00256 AC: 378 AN: 147534 Hom.: 0 Cov.: 30 AF XY: 0.00313 AC XY: 225 AN XY: 71880

Gnomad4 AFR AF: 0.000729

Gnomad4 AMR AF: 0.000336

Gnomad4 ASJ AF: 0.000589

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.00313

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00155

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BPTF: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

BPTF-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	9.4
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs906413939; hg19: chr17-65821975;