4-122893230-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_007083.5(NUDT6):c.554-5C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00813 in 1,582,192 control chromosomes in the GnomAD database, including 821 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (423 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (398 hom.)
• Consequence: NUDT6 NM_007083.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9262
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.337

Genes affected

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]

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 -10 ACMG points.

• BP6: Variant 4-122893230-G-T is Benign according to our data. Variant chr4-122893230-G-T is described in ClinVar as [Benign]. Clinvar id is 3056995.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF2	NM_001361665.2	c.*834G>T		3_prime_UTR_variant	3/3	ENST00000644866.2
NUDT6	NM_007083.5	c.554-5C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000304430.10
FGF2	NM_002006.6	c.*834G>T		3_prime_UTR_variant	3/3
NUDT6	NM_198041.3	c.47-5C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF2	ENST00000644866.2	c.*834G>T		3_prime_UTR_variant	3/3		NM_001361665.2	P1
NUDT6	ENST00000304430.10	c.554-5C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007083.5	P1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6295 AN: 151968 Hom.: 426 Cov.: 33

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0118 AC: 2660 AN: 225120 Hom.: 173 AF XY: 0.00878 AC XY: 1074 AN XY: 122322

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.00950

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000120

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000776

Gnomad OTH exome AF: 0.00770

GnomAD4 exome AF: 0.00459 AC: 6567 AN: 1430106 Hom.: 398 Cov.: 31 AF XY: 0.00398 AC XY: 2822 AN XY: 708328

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000160

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000436

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.0414 AC: 6303 AN: 152086 Hom.: 423 Cov.: 33 AF XY: 0.0397 AC XY: 2950 AN XY: 74338

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.00946 Hom.: 32

Bravo AF: 0.0463

Asia WGS AF: 0.00808 AC: 29 AN: 3478

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

Aug 10, 2019

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
BayesDel_noAF	Benign	-0.83
Cadd	Benign	18
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.72
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45625032; hg19: chr4-123814385;