chr17-67825830-A-G

Variant names:

• chr17-67825830-A-G
• NM_182641.4:c.106A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182641.4(BPTF):​c.106A>G​(p.Ile36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000023 in 871,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000023 (0 hom.)
• Consequence: BPTF NM_182641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0110
• 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: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061546028).

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.106A>G	p.Ile36Val	missense	Exon 1 of 28	NP_872579.2
	BPTF	NM_001439139.1		c.106A>G	p.Ile36Val	missense	Exon 1 of 29	NP_001426068.1
	BPTF	NM_001439140.1		c.106A>G	p.Ile36Val	missense	Exon 1 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.106A>G	p.Ile36Val	missense	Exon 1 of 28	ENSP00000307208.6	Q12830-2
	BPTF	ENST00000582467.2	TSL:5	c.106A>G	p.Ile36Val	missense	Exon 1 of 32	ENSP00000463776.2	J3QQK4
	BPTF	ENST00000321892.8	TSL:5	c.106A>G	p.Ile36Val	missense	Exon 1 of 30	ENSP00000315454.4	Q12830-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000230 AC: 2 AN: 871124 Hom.: 0 Cov.: 32 AF XY: 0.00000246 AC XY: 1 AN XY: 405990

African (AFR) AF: 0.00 AC: 0 AN: 16508

American (AMR) AF: 0.00 AC: 0 AN: 2310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6114

East Asian (EAS) AF: 0.00 AC: 0 AN: 5222

South Asian (SAS) AF: 0.00 AC: 0 AN: 17690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1810

European-Non Finnish (NFE) AF: 0.00000254 AC: 2 AN: 787456

Other (OTH) AF: 0.00 AC: 0 AN: 29542

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.68
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.011
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.13	N
REVEL	Benign	0.048
Sift	Benign	0.39	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.053
MutPred		0.15		Loss of catalytic residue at I36 (P = 0.0905)
MVP		0.36
MPC		0.92
ClinPred		0.071	T
GERP RS		0.057
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.083
Mutation Taster		=98/2	polymorphism

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

hg19: chr17-65821946;