Genetic Variant NM_002028.4:c.915G>A (chr14-65044403-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_002028.4(FNTB):c.915G>A(p.Ala305Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 1,612,936 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00074 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 9 hom. )

Consequence

FNTB
NM_002028.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -9.26

Publications

0 publications found

Variant links:

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]

FNTB links:

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]

CHURC1-FNTB links:

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

MAX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 14-65044403-G-A is Benign according to our data. Variant chr14-65044403-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2644328.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-9.26 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 9 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FNTB	NM_002028.4	MANE Select	c.915G>A	p.Ala305Ala	synonymous	Exon 9 of 12	NP_002019.1	A0A384MEJ5
CHURC1-FNTB	NM_001202559.1		c.1098G>A	p.Ala366Ala	synonymous	Exon 11 of 14	NP_001189488.1	B4DL54
CHURC1-FNTB	NM_001202558.2		c.777G>A	p.Ala259Ala	synonymous	Exon 10 of 13	NP_001189487.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FNTB	ENST00000246166.3	TSL:1 MANE Select	c.915G>A	p.Ala305Ala	synonymous	Exon 9 of 12	ENSP00000246166.2	P49356-1
CHURC1-FNTB	ENST00000549987.1	TSL:2	c.1017G>A	p.Ala339Ala	synonymous	Exon 11 of 14	ENSP00000447121.2	B4DL54
FNTB	ENST00000916264.1		c.1047G>A	p.Ala349Ala	synonymous	Exon 10 of 13	ENSP00000586323.1

Frequencies

GnomAD3 genomes

AF:

0.000742

AC:

113

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00135

AC:

336

AN:

249642

AF XY:

0.00128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000860

Gnomad ASJ exome

AF:

0.0233

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000458

Gnomad OTH exome

AF:

0.00349

GnomAD4 exome

AF:

0.000728

AC:

1063

AN:

1460596

Hom.:

Cov.:

AF XY:

0.000742

AC XY:

539

AN XY:

726572

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33444

American (AMR)

AF:

0.000967

AC:

AN:

44472

Ashkenazi Jewish (ASJ)

AF:

0.0251

AC:

655

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000210

AC:

233

AN:

1111552

Other (OTH)

AF:

0.00205

AC:

124

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

135

202

270

337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152340

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41582

American (AMR)

AF:

0.000719

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68036

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.000854

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000892

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.6

(source)

DANN

Benign

0.90

PhyloP100

-9.3

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over