rs4466998

Variant names:

• chr14-65008822-C-A
• rs4466998
• NM_002028.4:c.210-3495C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-65008822-C-A
• chr14-65008822-C-G

Variant summary

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

The NM_002028.4(FNTB):​c.210-3495C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 152,046 control chromosomes in the GnomAD database, including 23,736 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 0.55 (23736 hom., cov: 32)
• Consequence: FNTB NM_002028.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.537
• Publications: 29 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNTB	NM_002028.4	MANE Select	c.210-3495C>A		intron	N/A	NP_002019.1	A0A384MEJ5
	CHURC1-FNTB	NM_001202559.1		c.393-3495C>A		intron	N/A	NP_001189488.1	B4DL54
	CHURC1-FNTB	NM_001202558.2		c.72-3495C>A		intron	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.210-3495C>A		intron	N/A	ENSP00000246166.2	P49356-1
	CHURC1-FNTB	ENST00000549987.1	TSL:2	c.312-3495C>A		intron	N/A	ENSP00000447121.2	B4DL54
	FNTB	ENST00000916264.1		c.210-3495C>A		intron	N/A	ENSP00000586323.1

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83921 AN: 151930 Hom.: 23686 Cov.: 32

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.553 AC: 84042 AN: 152046 Hom.: 23736 Cov.: 32 AF XY: 0.554 AC XY: 41165 AN XY: 74310

African (AFR) AF: 0.658 AC: 27305 AN: 41470

American (AMR) AF: 0.540 AC: 8253 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1473 AN: 3470

East Asian (EAS) AF: 0.593 AC: 3055 AN: 5154

South Asian (SAS) AF: 0.424 AC: 2043 AN: 4820

European-Finnish (FIN) AF: 0.583 AC: 6162 AN: 10574

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.501 AC: 34029 AN: 67958

Other (OTH) AF: 0.506 AC: 1066 AN: 2108

Alfa AF: 0.513 Hom.: 59247

Bravo AF: 0.560

Asia WGS AF: 0.528 AC: 1837 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.52
DANN	Benign	0.43
PhyloP100		-0.54
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: rs4466998; hg19: chr14-65475540;