14-65035521-G-A

Variant names:

• chr14-65035521-G-A
• rs7155454
• NM_002028.4:c.692+2825G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002028.4(FNTB):​c.692+2825G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 151,738 control chromosomes in the GnomAD database, including 28,900 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (28900 hom., cov: 30)
• Consequence: FNTB NM_002028.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.80
• Publications: 19 publications found

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:42960): (CHURC1-FNTB readthrough) This locus represents naturally occurring read-through transcription between the neighboring CHURC1 (churchill domain containing 1) and FNTB (farnesyltransferase, CAAX box, beta) on chromosome 14. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Feb 2011]

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]

MAX Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• polydactyly-macrocephaly syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.13).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002028.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNTB	NM_002028.4	MANE Select	c.692+2825G>A		intron	N/A	NP_002019.1
	CHURC1-FNTB	NM_001202559.1		c.875+2825G>A		intron	N/A	NP_001189488.1
	CHURC1-FNTB	NM_001202558.2		c.554+2825G>A		intron	N/A	NP_001189487.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNTB	ENST00000246166.3	TSL:1 MANE Select	c.692+2825G>A		intron	N/A	ENSP00000246166.2
	CHURC1-FNTB	ENST00000549987.1	TSL:2	c.794+2825G>A		intron	N/A	ENSP00000447121.2
	MAX	ENST00000341653.6	TSL:2	c.172-29237C>T		intron	N/A	ENSP00000342482.2

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91039 AN: 151620 Hom.: 28834 Cov.: 30

Gnomad AFR AF: 0.812

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.544

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.601 AC: 91179 AN: 151738 Hom.: 28900 Cov.: 30 AF XY: 0.600 AC XY: 44446 AN XY: 74114

African (AFR) AF: 0.813 AC: 33613 AN: 41364

American (AMR) AF: 0.561 AC: 8554 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1463 AN: 3462

East Asian (EAS) AF: 0.623 AC: 3218 AN: 5166

South Asian (SAS) AF: 0.466 AC: 2236 AN: 4798

European-Finnish (FIN) AF: 0.583 AC: 6105 AN: 10474

Middle Eastern (MID) AF: 0.366 AC: 107 AN: 292

European-Non Finnish (NFE) AF: 0.503 AC: 34180 AN: 67926

Other (OTH) AF: 0.549 AC: 1152 AN: 2098

Alfa AF: 0.554 Hom.: 39457

Bravo AF: 0.615

Asia WGS AF: 0.574 AC: 1999 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.64
DANN	Benign	0.58
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs7155454; hg19: chr14-65502239;