16-4337423-A-G

Position:

chr16-4337423-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032575.3(GLIS2):c.1474A>G(p.Thr492Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 1,584,644 control chromosomes in the GnomAD database, including 1,809 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T492T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.062 ( 437 hom., cov: 33)

Exomes 𝑓: 0.037 ( 1372 hom. )

Consequence

GLIS2
NM_032575.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.977

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018239915).

BP6

Variant 16-4337423-A-G is Benign according to our data. Variant chr16-4337423-A-G is described in ClinVar as [Benign]. Clinvar id is 167149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-4337423-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLIS2	NM_032575.3 linkuse as main transcript	c.1474A>G	p.Thr492Ala	missense_variant	7/7	ENST00000433375.2	NP_115964.2
GLIS2	NM_001318918.2 linkuse as main transcript	c.1474A>G	p.Thr492Ala	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.1474A>G	p.Thr492Ala	missense_variant	7/7	1	NM_032575.3	ENSP00000395547	P1
	ENST00000574705.1 linkuse as main transcript	n.396T>C		non_coding_transcript_exon_variant	1/1
GLIS2	ENST00000262366.7 linkuse as main transcript	c.1474A>G	p.Thr492Ala	missense_variant	8/8	2		ENSP00000262366	P1
PAM16	ENST00000577031.5 linkuse as main transcript	c.291+3497T>C		intron_variant		4		ENSP00000459113

Frequencies

GnomAD3 genomes

AF:

0.0615

AC:

9351

AN:

152026

Hom.:

433

Cov.:

show subpopulations

Gnomad AFR

AF:

0.131

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.0462

Gnomad ASJ

AF:

0.0404

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0128

Gnomad FIN

AF:

0.0209

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0386

Gnomad OTH

AF:

0.0575

GnomAD3 exomes

AF:

0.0335

AC:

6581

AN:

196554

Hom.:

177

AF XY:

0.0315

AC XY:

3379

AN XY:

107412

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.0296

Gnomad ASJ exome

AF:

0.0295

Gnomad EAS exome

AF:

0.0000648

Gnomad SAS exome

AF:

0.0143

Gnomad FIN exome

AF:

0.0183

Gnomad NFE exome

AF:

0.0360

Gnomad OTH exome

AF:

0.0376

GnomAD4 exome

AF:

0.0374

AC:

53622

AN:

1432500

Hom.:

1372

Cov.:

AF XY:

0.0364

AC XY:

25866

AN XY:

710542

show subpopulations

Gnomad4 AFR exome

AF:

0.145

Gnomad4 AMR exome

AF:

0.0327

Gnomad4 ASJ exome

AF:

0.0308

Gnomad4 EAS exome

AF:

0.000156

Gnomad4 SAS exome

AF:

0.0138

Gnomad4 FIN exome

AF:

0.0203

Gnomad4 NFE exome

AF:

0.0381

Gnomad4 OTH exome

AF:

0.0407

GnomAD4 genome

AF:

0.0617

AC:

9386

AN:

152144

Hom.:

437

Cov.:

AF XY:

0.0598

AC XY:

4451

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.131

Gnomad4 AMR

AF:

0.0461

Gnomad4 ASJ

AF:

0.0404

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.0128

Gnomad4 FIN

AF:

0.0209

Gnomad4 NFE

AF:

0.0386

Gnomad4 OTH

AF:

0.0569

Alfa

AF:

0.0436

Hom.:

174

Bravo

AF:

0.0677

TwinsUK

AF:

0.0369

AC:

137

ALSPAC

AF:

0.0446

AC:

172

ESP6500AA

AF:

0.122

AC:

527

ESP6500EA

AF:

0.0314

AC:

268

ExAC

AF:

0.0280

AC:

3324

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Nephronophthisis 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.070

T;T

Eigen

Benign

0.045

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.66

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

0.00013

P;P;P

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.41

N;N

REVEL

Benign

0.070

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.17

T;T

Polyphen

0.37

B;B

Vest4

0.030

MPC

0.28

ClinPred

0.024

GERP RS

5.5

Varity_R

0.16

gMVP

0.51

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