17-67825870-G-C

Position:

• chr17-67825870-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_182641.4(BPTF):​c.146G>C​(p.Gly49Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 30)
• Consequence: BPTF NM_182641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.152

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.26669848).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPTF	NM_182641.4	c.146G>C	p.Gly49Ala	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.146G>C	p.Gly49Ala	missense_variant	1/28	1	NM_182641.4	ENSP00000307208.6
BPTF	ENST00000582467.2	c.146G>C	p.Gly49Ala	missense_variant	1/32	5		ENSP00000463776.2
BPTF	ENST00000321892.8	c.146G>C	p.Gly49Ala	missense_variant	1/30	5		ENSP00000315454.4
BPTF	ENST00000544778.6	c.146G>C	p.Gly49Ala	missense_variant	1/22	5		ENSP00000440854.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

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

May 09, 2023

The c.146G>C (p.G49A) alteration is located in exon 1 (coding exon 1) of the BPTF gene. This alteration results from a G to C substitution at nucleotide position 146, causing the glycine (G) at amino acid position 49 to be replaced by an alanine (A). 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	Pathogenic	0.75
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.66
DEOGEN2	Benign	0.15	.;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.49	T;T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.81	.;L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.1	.;N;N
REVEL	Benign	0.18
Sift	Benign	0.65	.;T;T
Sift4G	Benign	0.66	T;T;T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.12, 0.083
MutPred		0.26		Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);
MVP		0.82
MPC		1.2
ClinPred		0.18	T
GERP RS		1.2
Varity_R		0.076
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-65821986;