16-4337222-G-A

Position:

chr16-4337222-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032575.3(GLIS2):c.1273G>A(p.Gly425Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000165 in 1,547,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

GLIS2
NM_032575.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.43

Variant links:

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]

GLIS2 links:

(HGNC:):

links:

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]

PAM16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017530978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLIS2	NM_032575.3 linkuse as main transcript	c.1273G>A	p.Gly425Arg	missense_variant	7/7	ENST00000433375.2	NP_115964.2
GLIS2	NM_001318918.2 linkuse as main transcript	c.1273G>A	p.Gly425Arg	missense_variant	8/8		NP_001305847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GLIS2	ENST00000433375.2 linkuse as main transcript	c.1273G>A	p.Gly425Arg	missense_variant	7/7	1	NM_032575.3	ENSP00000395547	P1
	ENST00000574705.1 linkuse as main transcript	n.597C>T		non_coding_transcript_exon_variant	1/1
GLIS2	ENST00000262366.7 linkuse as main transcript	c.1273G>A	p.Gly425Arg	missense_variant	8/8	2		ENSP00000262366	P1
PAM16	ENST00000577031.5 linkuse as main transcript	c.291+3698C>T		intron_variant		4		ENSP00000459113

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

144756

Hom.:

AF XY:

0.000141

AC XY:

AN XY:

78176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000278

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000130

Gnomad OTH exome

AF:

0.000237

GnomAD4 exome

AF:

0.000173

AC:

241

AN:

1395300

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

130

AN XY:

688420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000364

Gnomad4 SAS exome

AF:

0.000177

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000193

Gnomad4 OTH exome

AF:

0.0000518

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000535

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephronophthisis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2021

This sequence change replaces glycine with arginine at codon 425 of the GLIS2 protein (p.Gly425Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. While this variant is present in population databases (rs199849300), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with GLIS2-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nephronophthisis 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.84

M_CAP

Benign

0.027

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

0.64

N;N;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.065

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.29

B;B

Vest4

0.41

MutPred

0.31

Gain of methylation at G425 (P = 0.0052);Gain of methylation at G425 (P = 0.0052);

MVP

0.068

MPC

0.34

ClinPred

0.13

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.23

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over