17-67825930-G-A

Position:

chr17-67825930-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_182641.4(BPTF):c.206G>A(p.Gly69Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,015,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000048 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

BPTF
NM_182641.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.15

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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=0.18495503).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPTF	NM_182641.4 linkuse as main transcript	c.206G>A	p.Gly69Glu	missense_variant	1/28	ENST00000306378.11	NP_872579.2	Q12830-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BPTF	ENST00000306378.11 linkuse as main transcript	c.206G>A	p.Gly69Glu	missense_variant	1/28	1	NM_182641.4	ENSP00000307208.6	Q12830-2
BPTF	ENST00000582467.2 linkuse as main transcript	c.206G>A	p.Gly69Glu	missense_variant	1/32	5		ENSP00000463776.2	J3QQK4
BPTF	ENST00000321892.8 linkuse as main transcript	c.206G>A	p.Gly69Glu	missense_variant	1/30	5		ENSP00000315454.4	Q12830-1
BPTF	ENST00000544778.6 linkuse as main transcript	c.206G>A	p.Gly69Glu	missense_variant	1/22	5		ENSP00000440854.2	F5GXF5

Frequencies

GnomAD3 genomes

AF:

0.0000475

AC:

AN:

147300

Hom.:

Cov.:

show subpopulations

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:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000757

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000276

AC:

AN:

868316

Hom.:

Cov.:

AF XY:

0.0000321

AC XY:

AN XY:

404450

show subpopulations

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:

0.0000293

Gnomad4 OTH exome

AF:

0.0000341

GnomAD4 genome

AF:

0.0000475

AC:

AN:

147300

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

71680

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000757

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

BPTF-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2022

The BPTF c.206G>A variant is predicted to result in the amino acid substitution p.Gly69Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.17

.;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.34

T;T;T

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

.;N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.4

.;N;N

REVEL

Benign

0.099

Sift

Uncertain

0.011

.;D;D

Sift4G

Uncertain

0.056

T;D;D

Polyphen

0.41, 0.71

.;B;P

Vest4

0.11, 0.096

MVP

0.51

MPC

1.4

ClinPred

0.15

GERP RS

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over