17-67825930-G-C

Position:

• chr17-67825930-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_182641.4(BPTF):​c.206G>C​(p.Gly69Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,015,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: BPTF NM_182641.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.15

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 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=0.18158293).
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPTF	NM_182641.4	c.206G>C	p.Gly69Ala	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.206G>C	p.Gly69Ala	missense_variant	1/28	1	NM_182641.4	ENSP00000307208.6
BPTF	ENST00000582467.2	c.206G>C	p.Gly69Ala	missense_variant	1/32	5		ENSP00000463776.2
BPTF	ENST00000321892.8	c.206G>C	p.Gly69Ala	missense_variant	1/30	5		ENSP00000315454.4
BPTF	ENST00000544778.6	c.206G>C	p.Gly69Ala	missense_variant	1/22	5		ENSP00000440854.2

Frequencies

GnomAD3 genomes AF: 0.0000611 AC: 9 AN: 147300 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000303

Gnomad OTH AF: 0.000492

GnomAD4 exome AF: 0.0000311 AC: 27 AN: 868316 Hom.: 0 Cov.: 31 AF XY: 0.0000494 AC XY: 20 AN XY: 404450

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000568

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000611 AC: 9 AN: 147408 Hom.: 0 Cov.: 30 AF XY: 0.0000418 AC XY: 3 AN XY: 71798

Gnomad4 AFR AF: 0.0000974

Gnomad4 AMR AF: 0.0000672

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000303

Gnomad4 OTH AF: 0.000486

Bravo AF: 0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.206G>C (p.G69A) 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 206, causing the glycine (G) at amino acid position 69 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.44
DEOGEN2	Benign	0.15	.;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.37	T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	.;N;N
REVEL	Benign	0.11
Sift	Benign	0.038	.;D;D
Sift4G	Benign	0.098	T;D;D
Polyphen		0.23, 0.50	.;B;P
Vest4		0.14, 0.093
MutPred		0.13		Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);
MVP		0.66
MPC		1.2
ClinPred		0.13	T
GERP RS		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.087
gMVP		0.24

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: rs1244643578; hg19: chr17-65822046;