4-122893009-G-A

Position:

chr4-122893009-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_007083.5(NUDT6):c.770C>T(p.Thr257Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00161 in 1,614,112 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 6 hom. )

Consequence

NUDT6
NM_007083.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.82

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043071806).

BP6

Variant 4-122893009-G-A is Benign according to our data. Variant chr4-122893009-G-A is described in ClinVar as [Benign]. Clinvar id is 3039263.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NUDT6	NM_007083.5 linkuse as main transcript	c.770C>T	p.Thr257Ile	missense_variant	5/5	ENST00000304430.10
FGF2	NM_001361665.2 linkuse as main transcript	c.*613G>A		3_prime_UTR_variant	3/3	ENST00000644866.2
NUDT6	NM_198041.3 linkuse as main transcript	c.263C>T	p.Thr88Ile	missense_variant	5/5
FGF2	NM_002006.6 linkuse as main transcript	c.*613G>A		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUDT6	ENST00000304430.10 linkuse as main transcript	c.770C>T	p.Thr257Ile	missense_variant	5/5	1	NM_007083.5	P1	P53370-1
FGF2	ENST00000644866.2 linkuse as main transcript	c.*613G>A		3_prime_UTR_variant	3/3		NM_001361665.2	P1	P09038-2

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00206

AC:

513

AN:

248966

Hom.:

AF XY:

0.00188

AC XY:

254

AN XY:

134768

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.00206

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00160

AC:

2345

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

1102

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.000918

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0131

Gnomad4 NFE exome

AF:

0.00137

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00168

AC:

256

AN:

152238

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0117

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.000778

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00215

AC:

261

EpiCase

AF:

0.00142

EpiControl

AF:

0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

NUDT6-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2020

This variant is classified as 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

0.17

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;.;.

Eigen

Benign

0.0059

Eigen_PC

Benign

-0.088

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.75

T;.;T

MetaRNN

Benign

0.0043

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.024

D;D;D

Sift4G

Benign

0.088

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.42

MVP

0.43

MPC

0.40

ClinPred

0.045

GERP RS

4.3

Varity_R

0.27

gMVP

0.59

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