4-122917603-A-G

Variant names:

• chr4-122917603-A-G
• rs12648093
• NM_007083.5:c.340T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007083.5(NUDT6):​c.340T>C​(p.Cys114Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 1,613,926 control chromosomes in the GnomAD database, including 429,207 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C114F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.62 (32345 hom., cov: 32)
  • Exomes 𝑓: 0.73 (396862 hom.)
• Consequence: NUDT6 NM_007083.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.918
• Publications: 41 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3558957E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT6	NM_007083.5	c.340T>C	p.Cys114Arg	missense_variant	Exon 2 of 5	ENST00000304430.10	NP_009014.2
NUDT6	NM_198041.3	c.-168T>C		5_prime_UTR_variant	Exon 2 of 5		NP_932158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT6	ENST00000304430.10	c.340T>C	p.Cys114Arg	missense_variant	Exon 2 of 5	1	NM_007083.5	ENSP00000306070.5

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93729 AN: 152004 Hom.: 32331 Cov.: 32

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.945

Gnomad SAS AF: 0.664

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.624

GnomAD2 exomes AF: 0.707 AC: 176491 AN: 249558 AF XY: 0.710

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.688

Gnomad ASJ exome AF: 0.673

Gnomad EAS exome AF: 0.952

Gnomad FIN exome AF: 0.791

Gnomad NFE exome AF: 0.733

Gnomad OTH exome AF: 0.699

GnomAD4 exome AF: 0.731 AC: 1069134 AN: 1461806 Hom.: 396862 Cov.: 56 AF XY: 0.730 AC XY: 530867 AN XY: 727202

African (AFR) AF: 0.264 AC: 8825 AN: 33476

American (AMR) AF: 0.684 AC: 30603 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 17425 AN: 26136

East Asian (EAS) AF: 0.941 AC: 37358 AN: 39700

South Asian (SAS) AF: 0.668 AC: 57646 AN: 86254

European-Finnish (FIN) AF: 0.793 AC: 42353 AN: 53418

Middle Eastern (MID) AF: 0.533 AC: 3071 AN: 5766

European-Non Finnish (NFE) AF: 0.746 AC: 829004 AN: 1111936

Other (OTH) AF: 0.709 AC: 42849 AN: 60396

GnomAD4 genome AF: 0.616 AC: 93771 AN: 152120 Hom.: 32345 Cov.: 32 AF XY: 0.623 AC XY: 46311 AN XY: 74364

African (AFR) AF: 0.283 AC: 11723 AN: 41466

American (AMR) AF: 0.682 AC: 10421 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2305 AN: 3470

East Asian (EAS) AF: 0.945 AC: 4901 AN: 5184

South Asian (SAS) AF: 0.665 AC: 3201 AN: 4816

European-Finnish (FIN) AF: 0.800 AC: 8471 AN: 10590

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.743 AC: 50497 AN: 67992

Other (OTH) AF: 0.628 AC: 1325 AN: 2110

Alfa AF: 0.703 Hom.: 193898

Bravo AF: 0.593

TwinsUK AF: 0.740 AC: 2745

ALSPAC AF: 0.748 AC: 2882

ESP6500AA AF: 0.325 AC: 1307

ESP6500EA AF: 0.745 AC: 6240

ExAC AF: 0.697 AC: 84306

Asia WGS AF: 0.758 AC: 2637 AN: 3478

EpiCase AF: 0.721

EpiControl AF: 0.725

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.015
DANN	Benign	0.24
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0000024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.91	L
PhyloP100		-0.92
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.84	N
REVEL	Benign	0.0080
Sift	Benign	0.52	T
Sift4G	Benign	0.52	T
Vest4		0.045
ClinPred		0.0051	T
GERP RS		-7.9
Varity_R		0.25
gMVP		0.72
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12648093; hg19: chr4-123838758; COSMIC: COSV58645888; COSMIC: COSV58645888;