4-122893015-G-A

Position:

chr4-122893015-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_007083.5(NUDT6):c.764C>T(p.Ala255Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

NUDT6
NM_007083.5 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.41

Variant links:

Genes affected

NUDT6 (HGNC:8053): (nudix hydrolase 6) This gene overlaps and lies on the opposite strand from FGF2 gene, and is thought to be the FGF2 antisense gene. The two genes are independently transcribed, and their expression shows an inverse relationship, suggesting that this antisense transcript may regulate FGF2 expression. This gene has also been shown to have hormone-regulatory and antiproliferative actions in the pituitary that are independent of FGF2 expression. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

NUDT6 links:

FGF2 (HGNC:3676): (fibroblast growth factor 2) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members bind heparin and possess broad mitogenic and angiogenic activities. This protein has been implicated in diverse biological processes, such as limb and nervous system development, wound healing, and tumor growth. The mRNA for this gene contains multiple polyadenylation sites, and is alternatively translated from non-AUG (CUG) and AUG initiation codons, resulting in five different isoforms with distinct properties. The CUG-initiated isoforms are localized in the nucleus and are responsible for the intracrine effect, whereas, the AUG-initiated form is mostly cytosolic and is responsible for the paracrine and autocrine effects of this FGF. [provided by RefSeq, Jul 2008]

FGF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.005494058).

BP6

Variant 4-122893015-G-A is Benign according to our data. Variant chr4-122893015-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3050768.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NUDT6	NM_007083.5 linkuse as main transcript	c.764C>T	p.Ala255Val	missense_variant	5/5	ENST00000304430.10	NP_009014.2
FGF2	NM_001361665.2 linkuse as main transcript	c.*619G>A		3_prime_UTR_variant	3/3	ENST00000644866.2	NP_001348594.1
NUDT6	NM_198041.3 linkuse as main transcript	c.257C>T	p.Ala86Val	missense_variant	5/5		NP_932158.1
FGF2	NM_002006.6 linkuse as main transcript	c.*619G>A		3_prime_UTR_variant	3/3		NP_001997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUDT6	ENST00000304430.10 linkuse as main transcript	c.764C>T	p.Ala255Val	missense_variant	5/5	1	NM_007083.5	ENSP00000306070	P1	P53370-1
FGF2	ENST00000644866.2 linkuse as main transcript	c.*619G>A		3_prime_UTR_variant	3/3		NM_001361665.2	ENSP00000494222	P1	P09038-2

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

148

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000237

AC:

AN:

248946

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

134756

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000739

AC:

108

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00218

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000972

AC:

148

AN:

152198

Hom.:

Cov.:

AF XY:

0.000981

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00325

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.00102

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000296

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NUDT6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.45

DEOGEN2

Benign

0.050

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.70

T;.;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.0055

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.3

L;.;.

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.088

Sift

Benign

0.78

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.32

B;.;.

Vest4

0.052

MVP

0.20

MPC

0.098

ClinPred

0.017

GERP RS

-3.6

Varity_R

0.26

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over