rs8057701

Positions:

• chr16-4337423-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.977

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]

(HGNC:):

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 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	c.1474A>G	p.Thr492Ala	missense_variant	7/7	ENST00000433375.2	NP_115964.2
GLIS2	NM_001318918.2	c.1474A>G	p.Thr492Ala	missense_variant	8/8		NP_001305847.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0615 AC: 9351 AN: 152026 Hom.: 433 Cov.: 33

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

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.: 34 AF XY: 0.0364 AC XY: 25866 AN XY: 710542

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.: 33 AF XY: 0.0598 AC XY: 4451 AN XY: 74394

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: 68 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T;T
Eigen	Benign	0.045
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.66	D
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.00013	P;P;P
PrimateAI	Uncertain	0.57	T
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	T
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

Other links and lift over

dbSNP: rs8057701; hg19: chr16-4387424; COSMIC: COSV52110973; COSMIC: COSV52110973;