4-122922518-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007083.5(NUDT6):c.55G>C(p.Gly19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,608,402 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (32 hom.)
• Consequence: NUDT6 NM_007083.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.08

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00213027).
• BP6: Variant 4-122922518-C-G is Benign according to our data. Variant chr4-122922518-C-G is described in ClinVar as [Benign]. Clinvar id is 3037688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1831/152332) while in subpopulation AFR AF= 0.0409 (1701/41582). AF 95% confidence interval is 0.0393. There are 40 homozygotes in gnomad4. There are 857 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUDT6	NM_007083.5	c.55G>C	p.Gly19Arg	missense_variant	1/5	ENST00000304430.10
NUDT6	NM_198041.3	c.-270+283G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUDT6	ENST00000304430.10	c.55G>C	p.Gly19Arg	missense_variant	1/5	1	NM_007083.5	P1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1825 AN: 152214 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00378 AC: 886 AN: 234242 Hom.: 18 AF XY: 0.00293 AC XY: 379 AN XY: 129238

Gnomad AFR exome AF: 0.0493

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00786

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.00225

GnomAD4 exome AF: 0.00143 AC: 2077 AN: 1456070 Hom.: 32 Cov.: 29 AF XY: 0.00124 AC XY: 896 AN XY: 724500

Gnomad4 AFR exome AF: 0.0419

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00706

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.00322

GnomAD4 genome AF: 0.0120 AC: 1831 AN: 152332 Hom.: 40 Cov.: 32 AF XY: 0.0115 AC XY: 857 AN XY: 74492

Gnomad4 AFR AF: 0.0409

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00411 Hom.: 5

Bravo AF: 0.0132

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0395 AC: 148

ESP6500EA AF: 0.000742 AC: 6

ExAC AF: 0.00406 AC: 487

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NUDT6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 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	0.087
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.030
Dann	Benign	0.85
DEOGEN2	Benign	0.048	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.013
Sift	Benign	0.044	D
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.084
MVP		0.072
MPC		0.12
ClinPred		0.0055	T
GERP RS		-7.9
Varity_R		0.071
gMVP		0.40

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: rs114290529; hg19: chr4-123843673;