NM_002028.4:c.209+1976G>T

Variant names:

• chr14-65006289-G-T
• rs201052112
• NM_002028.4:c.209+1976G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002028.4(FNTB):​c.209+1976G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,612,710 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: FNTB NM_002028.4 intron
• Scores: Splicing: ADA: 0.00003429
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.241
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-65006289-G-T is Benign according to our data. Variant chr14-65006289-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1692098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.209+1976G>T		intron	N/A	NP_002019.1	A0A384MEJ5
	CHURC1-FNTB	NM_001202559.1		c.392+1976G>T		intron	N/A	NP_001189488.1	B4DL54
	CHURC1-FNTB	NM_001202558.2		c.71+1976G>T		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.209+1976G>T		intron	N/A	ENSP00000246166.2	P49356-1
	CHURC1-FNTB	ENST00000549987.1	TSL:2	c.311+1976G>T		intron	N/A	ENSP00000447121.2	B4DL54
	FNTB	ENST00000916264.1		c.209+1976G>T		intron	N/A	ENSP00000586323.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 151996 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000824

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000433 AC: 108 AN: 249592 AF XY: 0.000475

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000787

Gnomad NFE exome AF: 0.000725

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000595 AC: 869 AN: 1460714 Hom.: 2 Cov.: 35 AF XY: 0.000549 AC XY: 399 AN XY: 726604

African (AFR) AF: 0.000120 AC: 4 AN: 33376

American (AMR) AF: 0.0000900 AC: 4 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85906

European-Finnish (FIN) AF: 0.000787 AC: 42 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000700 AC: 778 AN: 1111712

Other (OTH) AF: 0.000679 AC: 41 AN: 60352

GnomAD4 genome AF: 0.000447 AC: 68 AN: 151996 Hom.: 0 Cov.: 31 AF XY: 0.000364 AC XY: 27 AN XY: 74230

African (AFR) AF: 0.0000967 AC: 4 AN: 41368

American (AMR) AF: 0.000131 AC: 2 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000473 AC: 5 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000824 AC: 56 AN: 67996

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000518 Hom.: 0

Bravo AF: 0.000355

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	MAX-related disorder (1)
-	-	1	not provided (1)
-	-	1	Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.1
DANN	Benign	0.72
PhyloP100		-0.24
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
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: rs201052112; hg19: chr14-65473007;