4-122893153-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007083.5(NUDT6):c.626G>A(p.Arg209Gln) variant causes a missense change. The variant allele was found at a frequency of 0.188 in 1,613,870 control chromosomes in the GnomAD database, including 32,714 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2452 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30262 hom.)
• Consequence: NUDT6 NM_007083.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.09

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055366755).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUDT6	NM_007083.5	c.626G>A	p.Arg209Gln	missense_variant	5/5	ENST00000304430.10
FGF2	NM_001361665.2	c.*757C>T		3_prime_UTR_variant	3/3	ENST00000644866.2
NUDT6	NM_198041.3	c.119G>A	p.Arg40Gln	missense_variant	5/5
FGF2	NM_002006.6	c.*757C>T		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUDT6	ENST00000304430.10	c.626G>A	p.Arg209Gln	missense_variant	5/5	1	NM_007083.5	P1
FGF2	ENST00000644866.2	c.*757C>T		3_prime_UTR_variant	3/3		NM_001361665.2	P1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24297 AN: 151994 Hom.: 2452 Cov.: 32

Gnomad AFR AF: 0.0580

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.142

GnomAD3 exomes AF: 0.211 AC: 52742 AN: 250426 Hom.: 6942 AF XY: 0.220 AC XY: 29776 AN XY: 135476

Gnomad AFR exome AF: 0.0562

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.471

Gnomad SAS exome AF: 0.368

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.191 AC: 279367 AN: 1461756 Hom.: 30262 Cov.: 33 AF XY: 0.197 AC XY: 143040 AN XY: 727178

Gnomad4 AFR exome AF: 0.0525

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.370

Gnomad4 FIN exome AF: 0.193

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.160 AC: 24308 AN: 152114 Hom.: 2452 Cov.: 32 AF XY: 0.169 AC XY: 12601 AN XY: 74362

Gnomad4 AFR AF: 0.0580

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.450

Gnomad4 SAS AF: 0.367

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.145

Alfa AF: 0.175 Hom.: 6387

Bravo AF: 0.146

TwinsUK AF: 0.169 AC: 628

ALSPAC AF: 0.167 AC: 645

ESP6500AA AF: 0.0656 AC: 289

ESP6500EA AF: 0.175 AC: 1501

ExAC AF: 0.208 AC: 25309

Asia WGS AF: 0.334 AC: 1161 AN: 3478

EpiCase AF: 0.172

EpiControl AF: 0.164

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;.;T
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	4.2e-9	P;P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.52
MPC		0.54
ClinPred		0.037	T
GERP RS		5.4
Varity_R		0.96
gMVP		0.82

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

Other links and lift over

dbSNP: rs1048201; hg19: chr4-123814308; COSMIC: COSV52648483; COSMIC: COSV52648483;