14-65012397-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002028.4(FNTB):c.282+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,613,984 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 32)
  • Exomes 𝑓: 0.014 (200 hom.)
• Consequence: FNTB NM_002028.4 splice_region, intron
• Scores: Splicing: ADA: 0.00008111
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.855

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-65012397-C-A is Benign according to our data. Variant chr14-65012397-C-A is described in ClinVar as [Benign]. Clinvar id is 1802848.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0103 (1565/152326) while in subpopulation SAS AF= 0.024 (116/4830). AF 95% confidence interval is 0.0205. There are 11 homozygotes in gnomad4. There are 783 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FNTB	NM_002028.4	c.282+8C>A		splice_region_variant, intron_variant		ENST00000246166.3
CHURC1-FNTB	NM_001202559.1	c.465+8C>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FNTB	ENST00000246166.3	c.282+8C>A		splice_region_variant, intron_variant		1	NM_002028.4	P1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1562 AN: 152208 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0131 AC: 3296 AN: 251076 Hom.: 46 AF XY: 0.0144 AC XY: 1948 AN XY: 135690

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00911

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0267

Gnomad FIN exome AF: 0.00822

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0136 AC: 19847 AN: 1461658 Hom.: 200 Cov.: 31 AF XY: 0.0141 AC XY: 10231 AN XY: 727136

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00917

Gnomad4 ASJ exome AF: 0.0308

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0275

Gnomad4 FIN exome AF: 0.00878

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.0103 AC: 1565 AN: 152326 Hom.: 11 Cov.: 32 AF XY: 0.0105 AC XY: 783 AN XY: 74484

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0240

Gnomad4 FIN AF: 0.00734

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0132 Hom.: 7

Bravo AF: 0.00946

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.37
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000081
dbscSNV1_RF	Benign	0.0040
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: rs56118026; hg19: chr14-65479115;