4-122917620-G-C

Variant names:

• chr4-122917620-G-C
• rs751383835
• NM_007083.5:c.323C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007083.5(NUDT6):​c.323C>G​(p.Ala108Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A108V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NUDT6 NM_007083.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.38
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007083.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT6	NM_007083.5	MANE Select	c.323C>G	p.Ala108Gly	missense	Exon 2 of 5	NP_009014.2
	NUDT6	NM_198041.3		c.-185C>G		5_prime_UTR	Exon 2 of 5	NP_932158.1	P53370-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT6	ENST00000304430.10	TSL:1 MANE Select	c.323C>G	p.Ala108Gly	missense	Exon 2 of 5	ENSP00000306070.5	P53370-1
	NUDT6	ENST00000339154.6	TSL:1	c.-185C>G		5_prime_UTR	Exon 2 of 5	ENSP00000344011.2	P53370-2
	NUDT6	ENST00000510735.1	TSL:5	c.106+4715C>G		intron	N/A	ENSP00000423745.1	H0Y9C0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		8.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.43		Gain of catalytic residue at A108 (P = 0.1788)
MVP		0.62
MPC		0.50
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.76
gMVP		0.66
Mutation Taster		=36/64	disease causing

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: rs751383835; hg19: chr4-123838775;