chr14-65053272-C-A

Variant names:

• chr14-65053272-C-A
• rs34156365
• NM_002028.4:c.990C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002028.4(FNTB):​c.990C>A​(p.Phe330Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,248 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F330F) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: FNTB NM_002028.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.347
• Publications: 0 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: ClinGen, Orphanet
• pheochromocytoma

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNTB	NM_002028.4	MANE Select	c.990C>A	p.Phe330Leu	missense	Exon 10 of 12	NP_002019.1	A0A384MEJ5
	CHURC1-FNTB	NM_001202559.1		c.1173C>A	p.Phe391Leu	missense	Exon 12 of 14	NP_001189488.1	B4DL54
	CHURC1-FNTB	NM_001202558.2		c.852C>A	p.Phe284Leu	missense	Exon 11 of 13	NP_001189487.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNTB	ENST00000246166.3	TSL:1 MANE Select	c.990C>A	p.Phe330Leu	missense	Exon 10 of 12	ENSP00000246166.2	P49356-1
	CHURC1-FNTB	ENST00000549987.1	TSL:2	c.1092C>A	p.Phe364Leu	missense	Exon 12 of 14	ENSP00000447121.2	B4DL54
	FNTB	ENST00000916264.1		c.1122C>A	p.Phe374Leu	missense	Exon 11 of 13	ENSP00000586323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303248 Hom.: 0 Cov.: 30 AF XY: 0.00000156 AC XY: 1 AN XY: 642610

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27666

American (AMR) AF: 0.00 AC: 0 AN: 27776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20474

East Asian (EAS) AF: 0.00 AC: 0 AN: 32390

South Asian (SAS) AF: 0.00 AC: 0 AN: 62166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5156

European-Non Finnish (NFE) AF: 9.74e-7 AC: 1 AN: 1026648

Other (OTH) AF: 0.00 AC: 0 AN: 52464

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	0.043
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		-0.35
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.53		Gain of catalytic residue at W362 (P = 0.0017)
MVP		0.25
MPC		1.2
ClinPred		0.98	D
GERP RS		0.90
Varity_R		0.91
gMVP		0.66
Mutation Taster		=17/83	disease causing

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: rs34156365; hg19: chr14-65519990;