chr14-65006156-C-CTT

Variant names:

• chr14-65006156-C-CTT
• rs367570902
• NM_002028.4:c.209+1859_209+1860dupTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_197957.4(MAX):​c.*46_*47dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1243 hom., cov: 0)
  • Exomes 𝑓: 0.069 (35 hom.)
• Consequence: MAX NM_197957.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.672
• 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 -10 ACMG points.

• BP6: Variant 14-65006156-C-CTT is Benign according to our data. Variant chr14-65006156-C-CTT is described in ClinVar as Benign. ClinVar VariationId is 1245444.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_197957.4. 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+1859_209+1860dupTT		intron	N/A	NP_002019.1	A0A384MEJ5
	MAX	NM_197957.4		c.*46_*47dupAA		3_prime_UTR	Exon 4 of 4	NP_932061.1	P61244-6
	MAX	NM_001271069.2		c.*46_*47dupAA		3_prime_UTR	Exon 3 of 3	NP_001257998.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNTB	ENST00000246166.3	TSL:1 MANE Select	c.209+1843_209+1844insTT		intron	N/A	ENSP00000246166.2	P49356-1
	CHURC1-FNTB	ENST00000549987.1	TSL:2	c.311+1843_311+1844insTT		intron	N/A	ENSP00000447121.2	B4DL54
	FNTB	ENST00000916264.1		c.209+1843_209+1844insTT		intron	N/A	ENSP00000586323.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 17149 AN: 133352 Hom.: 1240 Cov.: 0

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0752

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.122

GnomAD4 exome AF: 0.0688 AC: 91967 AN: 1336218 Hom.: 35 Cov.: 0 AF XY: 0.0669 AC XY: 44536 AN XY: 665586

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0355 AC: 1053 AN: 29648

American (AMR) AF: 0.0640 AC: 2260 AN: 35306

Ashkenazi Jewish (ASJ) AF: 0.0328 AC: 782 AN: 23822

East Asian (EAS) AF: 0.0506 AC: 1842 AN: 36380

South Asian (SAS) AF: 0.0430 AC: 3324 AN: 77302

European-Finnish (FIN) AF: 0.0531 AC: 2245 AN: 42246

Middle Eastern (MID) AF: 0.0250 AC: 125 AN: 4998

European-Non Finnish (NFE) AF: 0.0748 AC: 77096 AN: 1031296

Other (OTH) AF: 0.0587 AC: 3240 AN: 55220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.129 AC: 17157 AN: 133324 Hom.: 1243 Cov.: 0 AF XY: 0.129 AC XY: 8225 AN XY: 63754

African (AFR) AF: 0.0795 AC: 2885 AN: 36300

American (AMR) AF: 0.185 AC: 2473 AN: 13380

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 311 AN: 3254

East Asian (EAS) AF: 0.128 AC: 598 AN: 4680

South Asian (SAS) AF: 0.128 AC: 526 AN: 4122

European-Finnish (FIN) AF: 0.145 AC: 895 AN: 6156

Middle Eastern (MID) AF: 0.0750 AC: 18 AN: 240

European-Non Finnish (NFE) AF: 0.146 AC: 9137 AN: 62506

Other (OTH) AF: 0.124 AC: 228 AN: 1832

Alfa AF: 0.0526 Hom.: 190

ClinVar

ClinVar submissions

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
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs367570902; hg19: chr14-65472874;