chr8-28033631-C-T

Position:

• chr8-28033631-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001010906.2(NUGGC):​c.1678G>A​(p.Ala560Thr) 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. 13/21 in silico tools predict a benign 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. A560P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUGGC NM_001010906.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

Genes affected

NUGGC (HGNC:33550): (nuclear GTPase, germinal center associated) Enables GTPase activity. Involved in cellular response to lipopolysaccharide; negative regulation of apoptotic process; and regulation of nuclear cell cycle DNA replication. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27830186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUGGC	NM_001010906.2	c.1678G>A	p.Ala560Thr	missense_variant	14/19	ENST00000413272.7
NUGGC	XM_011544523.3	c.1750G>A	p.Ala584Thr	missense_variant	14/19
NUGGC	XM_011544524.4	c.1750G>A	p.Ala584Thr	missense_variant	14/19
NUGGC	XM_011544525.2	c.517G>A	p.Ala173Thr	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUGGC	ENST00000413272.7	c.1678G>A	p.Ala560Thr	missense_variant	14/19	5	NM_001010906.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.1678G>A (p.A560T) alteration is located in exon 14 (coding exon 13) of the NUGGC gene. This alteration results from a G to A substitution at nucleotide position 1678, causing the alanine (A) at amino acid position 560 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.031
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.89	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.073
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.23	B
Vest4		0.57
MutPred		0.29		Gain of loop (P = 0.069);
MVP		0.26
MPC		0.17
ClinPred		0.46	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-27891148; COSMIC: COSV100429218;