16-4332351-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032575.3(GLIS2):c.71G>A(p.Arg24Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,460,812 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Synonymous variant affecting the same amino acid position (i.e. R24R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: GLIS2 NM_032575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

Genes affected

GLIS2 (HGNC:29450): (GLIS family zinc finger 2) This gene is a member of the GLI-similar zinc finger protein family and encodes a nuclear transcription factor with five C2H2-type zinc finger domains. The protein encoded by this gene is widely expressed at low levels in the neural tube and peripheral nervous system and likely promotes neuronal differentiation. It is abundantly expressed in the kidney and may have a role in the regulation of kidney morphogenesis. p120 regulates the expression level of this protein and induces the cleavage of this protein's C-terminal zinc finger domain. This protein also promotes the nuclear translocation of p120. Mutations in this gene cause nephronophthisis (NPHP), an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial lymphohistiocytic cell infiltration, and development of cysts at the corticomedullary border of the kidneys.[provided by RefSeq, Jan 2010]

PAM16 (HGNC:29679): (presequence translocase associated motor 16) This gene encodes a mitochondrial protein involved in granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. This protein also plays a role in the import of nuclear-encoded mitochondrial proteins into the mitochondrial matrix and may be important in reactive oxygen species (ROS) homeostasis. Mutations in this gene cause Megarbane-Dagher-Melike type spondylometaphyseal dysplasia, an early lethal skeletal dysplasia characterized by short stature, developmental delay and other skeletal abnormalities. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0680013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS2	NM_032575.3	c.71G>A	p.Arg24Gln	missense_variant	2/7	ENST00000433375.2
GLIS2	NM_001318918.2	c.71G>A	p.Arg24Gln	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS2	ENST00000433375.2	c.71G>A	p.Arg24Gln	missense_variant	2/7	1	NM_032575.3	P1
GLIS2	ENST00000262366.7	c.71G>A	p.Arg24Gln	missense_variant	3/8	2		P1
PAM16	ENST00000577031.5	c.292-577C>T		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 248992 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460812 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 726712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Jun 29, 2022

The c.71G>A (p.R24Q) alteration is located in exon 1 (coding exon 1) of the GLIS2 gene. This alteration results from a G to A substitution at nucleotide position 71, causing the arginine (R) at amino acid position 24 to be replaced by a glutamine (Q). 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	0.22
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.51	N;N
MutationTaster	Benign	0.78	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.068
Sift	Benign	0.076	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.016	B;B
Vest4		0.087
MutPred		0.18		Loss of MoRF binding (P = 0.0987);Loss of MoRF binding (P = 0.0987);
MVP		0.082
MPC		0.33
ClinPred		0.070	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.25

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: rs774305330; hg19: chr16-4382352;