4-122893015-G-C

Variant names:

• chr4-122893015-G-C
• rs138619142
• NM_007083.5:c.764C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007083.5(NUDT6):​c.764C>G​(p.Ala255Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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. A255V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NUDT6 NM_007083.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 1 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]

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2459966).

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.764C>G	p.Ala255Gly	missense	Exon 5 of 5	NP_009014.2
	FGF2	NM_001361665.2	MANE Select	c.*619G>C		3_prime_UTR	Exon 3 of 3	NP_001348594.1	D9ZGF5
	NUDT6	NM_198041.3		c.257C>G	p.Ala86Gly	missense	Exon 5 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.764C>G	p.Ala255Gly	missense	Exon 5 of 5	ENSP00000306070.5	P53370-1
	NUDT6	ENST00000339154.6	TSL:1	c.257C>G	p.Ala86Gly	missense	Exon 5 of 5	ENSP00000344011.2	P53370-2
	FGF2	ENST00000644866.2	MANE Select	c.*619G>C		3_prime_UTR	Exon 3 of 3	ENSP00000494222.1	P09038-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.90	P
Vest4		0.098
MutPred		0.58		Gain of glycosylation at T257 (P = 0.0489)
MVP		0.37
MPC		0.26
ClinPred		0.97	D
GERP RS		-3.6
Varity_R		0.82
gMVP		0.44
Mutation Taster		=67/33	polymorphism

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: rs138619142; hg19: chr4-123814170;