NM_182641.4:c.92C>G

Variant names:

• chr17-67825816-C-G
• rs2055938658
• NM_182641.4:c.92C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_182641.4(BPTF):​c.92C>G​(p.Pro31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 877,098 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: BPTF NM_182641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31774336).

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.92C>G	p.Pro31Arg	missense	Exon 1 of 28	NP_872579.2
	BPTF	NM_001439139.1		c.92C>G	p.Pro31Arg	missense	Exon 1 of 29	NP_001426068.1
	BPTF	NM_001439140.1		c.92C>G	p.Pro31Arg	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.92C>G	p.Pro31Arg	missense	Exon 1 of 28	ENSP00000307208.6	Q12830-2
	BPTF	ENST00000582467.2	TSL:5	c.92C>G	p.Pro31Arg	missense	Exon 1 of 32	ENSP00000463776.2	J3QQK4
	BPTF	ENST00000321892.8	TSL:5	c.92C>G	p.Pro31Arg	missense	Exon 1 of 30	ENSP00000315454.4	Q12830-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000456 AC: 4 AN: 877098 Hom.: 0 Cov.: 31 AF XY: 0.00000244 AC XY: 1 AN XY: 409296

African (AFR) AF: 0.00 AC: 0 AN: 16620

American (AMR) AF: 0.00 AC: 0 AN: 2500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6294

East Asian (EAS) AF: 0.00 AC: 0 AN: 5548

South Asian (SAS) AF: 0.00 AC: 0 AN: 17728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1834

European-Non Finnish (NFE) AF: 0.00000505 AC: 4 AN: 791562

Other (OTH) AF: 0.00 AC: 0 AN: 29936

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.0028
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.36	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.28
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.22
MutPred		0.24		Loss of glycosylation at P31 (P = 0.0022)
MVP		0.59
MPC		1.1
ClinPred		0.27	T
GERP RS		1.2
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.26
Mutation Taster		=86/14	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

dbSNP: rs2055938658; hg19: chr17-65821932;