chr14-65006478-G-A

Variant names:

• chr14-65006478-G-A
• rs7148590
• NM_002028.4:c.209+2165G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002028.4(FNTB):​c.209+2165G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 152,034 control chromosomes in the GnomAD database, including 24,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.56 (24732 hom., cov: 32)
• Consequence: FNTB NM_002028.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.561
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 14-65006478-G-A is Benign according to our data. Variant chr14-65006478-G-A is described in ClinVar as Benign. ClinVar VariationId is 1233970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNTB	NM_002028.4	c.209+2165G>A		intron_variant	Intron 2 of 11	ENST00000246166.3	NP_002019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNTB	ENST00000246166.3	c.209+2165G>A		intron_variant	Intron 2 of 11	1	NM_002028.4	ENSP00000246166.2
CHURC1-FNTB	ENST00000549987.1	c.311+2165G>A		intron_variant	Intron 4 of 13	2		ENSP00000447121.2

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85513 AN: 151914 Hom.: 24685 Cov.: 32

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.511

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

GnomAD4 genome AF: 0.563 AC: 85636 AN: 152034 Hom.: 24732 Cov.: 32 AF XY: 0.564 AC XY: 41931 AN XY: 74308

African (AFR) AF: 0.690 AC: 28579 AN: 41438

American (AMR) AF: 0.544 AC: 8317 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1526 AN: 3470

East Asian (EAS) AF: 0.593 AC: 3065 AN: 5170

South Asian (SAS) AF: 0.441 AC: 2127 AN: 4822

European-Finnish (FIN) AF: 0.582 AC: 6161 AN: 10578

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34115 AN: 67966

Other (OTH) AF: 0.517 AC: 1090 AN: 2110

Alfa AF: 0.534 Hom.: 7326

Bravo AF: 0.572

Asia WGS AF: 0.536 AC: 1866 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.17
DANN	Benign	0.47
PhyloP100		-0.56
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: rs7148590; hg19: chr14-65473196;