chr14-65032614-GCA-TCC

Variant names:

• chr14-65032614-GCA-TCC
• NM_002028.4:c.610_612delGCAinsTCC
• FNTB p.Ala204Ser

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_002028.4(FNTB):​c.610_612delGCAinsTCC​(p.Ala204Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FNTB NM_002028.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• 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: Orphanet, ClinGen
• pheochromocytoma

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.610_612delGCAinsTCC	p.Ala204Ser	missense	N/A	NP_002019.1	A0A384MEJ5
	CHURC1-FNTB	NM_001202559.1		c.793_795delGCAinsTCC	p.Ala265Ser	missense	N/A	NP_001189488.1	B4DL54
	CHURC1-FNTB	NM_001202558.2		c.472_474delGCAinsTCC	p.Ala158Ser	missense	N/A	NP_001189487.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNTB	ENST00000246166.3	TSL:1 MANE Select	c.610_612delGCAinsTCC	p.Ala204Ser	missense	N/A	ENSP00000246166.2	P49356-1
	CHURC1-FNTB	ENST00000549987.1	TSL:2	c.712_714delGCAinsTCC	p.Ala238Ser	missense	N/A	ENSP00000447121.2	B4DL54
	FNTB	ENST00000916264.1		c.742_744delGCAinsTCC	p.Ala248Ser	missense	N/A	ENSP00000586323.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-65499332;