14-65032594-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_002028.4(FNTB):c.606-16G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,612,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: FNTB NM_002028.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.189

Genes affected

FNTB (HGNC:3785): (farnesyltransferase, CAAX box, beta) Enables zinc ion binding activity. Contributes to protein farnesyltransferase activity. Involved in protein farnesylation. Part of microtubule associated complex and protein farnesyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

CHURC1-FNTB (HGNC:):

MAX (HGNC:6913): (MYC associated factor X) The protein encoded by this gene is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family of transcription factors. It is able to form homodimers and heterodimers with other family members, which include Mad, Mxi1 and Myc. Myc is an oncoprotein implicated in cell proliferation, differentiation and apoptosis. The homodimers and heterodimers compete for a common DNA target site (the E box) and rearrangement among these dimer forms provides a complex system of transcriptional regulation. Mutations of this gene have been reported to be associated with hereditary pheochromocytoma. A pseudogene of this gene is located on the long arm of chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-65032594-G-A is Benign according to our data. Variant chr14-65032594-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2575320.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FNTB	NM_002028.4	c.606-16G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000246166.3
CHURC1-FNTB	NM_001202559.1	c.789-16G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FNTB	ENST00000246166.3	c.606-16G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002028.4	P1
MAX	ENST00000341653.6	c.172-26310C>T		intron_variant		2
FNTB	ENST00000554334.5	n.574-16G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
FNTB	ENST00000556709.1	n.385-16G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000413 AC: 103 AN: 249694 Hom.: 0 AF XY: 0.000444 AC XY: 60 AN XY: 135028

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000230

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.000654

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000668 AC: 976 AN: 1460174 Hom.: 0 Cov.: 30 AF XY: 0.000662 AC XY: 481 AN XY: 726444

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000456

Gnomad4 NFE exome AF: 0.000801

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74472

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.000374

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	3.0
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200759729; hg19: chr14-65499312;