14-65053272-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_002028.4(FNTB):​c.990C>T​(p.Phe330Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,455,536 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0085 (10 hom., cov: 32)
  • Exomes 𝑓: 0.014 (124 hom.)
• Consequence: FNTB NM_002028.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.347
• Publications: 5 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 14-65053272-C-T is Benign according to our data. Variant chr14-65053272-C-T is described in ClinVar as Benign. ClinVar VariationId is 2644329.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.347 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0138 (17999/1303190) while in subpopulation NFE AF = 0.0158 (16252/1026606). AF 95% confidence interval is 0.0156. There are 124 homozygotes in GnomAdExome4. There are 8671 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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>T	p.Phe330Phe	synonymous	Exon 10 of 12	NP_002019.1	A0A384MEJ5
	CHURC1-FNTB	NM_001202559.1		c.1173C>T	p.Phe391Phe	synonymous	Exon 12 of 14	NP_001189488.1	B4DL54
	CHURC1-FNTB	NM_001202558.2		c.852C>T	p.Phe284Phe	synonymous	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>T	p.Phe330Phe	synonymous	Exon 10 of 12	ENSP00000246166.2	P49356-1
	CHURC1-FNTB	ENST00000549987.1	TSL:2	c.1092C>T	p.Phe364Phe	synonymous	Exon 12 of 14	ENSP00000447121.2	B4DL54
	FNTB	ENST00000916264.1		c.1122C>T	p.Phe374Phe	synonymous	Exon 11 of 13	ENSP00000586323.1

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1300 AN: 152228 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00875 AC: 1458 AN: 166700 AF XY: 0.00914

Gnomad AFR exome AF: 0.00189

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0000975

Gnomad FIN exome AF: 0.00637

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.00634

GnomAD4 exome AF: 0.0138 AC: 17999 AN: 1303190 Hom.: 124 Cov.: 30 AF XY: 0.0135 AC XY: 8671 AN XY: 642576

African (AFR) AF: 0.00188 AC: 52 AN: 27666

American (AMR) AF: 0.00266 AC: 74 AN: 27776

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 71 AN: 20472

East Asian (EAS) AF: 0.0000926 AC: 3 AN: 32390

South Asian (SAS) AF: 0.00848 AC: 527 AN: 62158

European-Finnish (FIN) AF: 0.00635 AC: 308 AN: 48504

Middle Eastern (MID) AF: 0.00737 AC: 38 AN: 5156

European-Non Finnish (NFE) AF: 0.0158 AC: 16252 AN: 1026606

Other (OTH) AF: 0.0128 AC: 674 AN: 52462

GnomAD4 genome AF: 0.00853 AC: 1300 AN: 152346 Hom.: 10 Cov.: 32 AF XY: 0.00784 AC XY: 584 AN XY: 74496

African (AFR) AF: 0.00286 AC: 119 AN: 41590

American (AMR) AF: 0.00346 AC: 53 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1018 AN: 68030

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.0132 Hom.: 30

Bravo AF: 0.00806

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.5
DANN	Benign	0.78
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;