rs140403969

Positions:

• chr16-4337425-G-A
• chr16-4337425-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_032575.3(GLIS2):​c.1476G>A​(p.Thr492Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00847 in 1,584,854 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (75 hom.)
• Consequence: GLIS2 NM_032575.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.37

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]

ENSG00000262712 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-4337425-G-A is Benign according to our data. Variant chr16-4337425-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 319225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-4337425-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.37 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLIS2	NM_032575.3	c.1476G>A	p.Thr492Thr	synonymous_variant	7/7	ENST00000433375.2	NP_115964.2
GLIS2	NM_001318918.2	c.1476G>A	p.Thr492Thr	synonymous_variant	8/8		NP_001305847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLIS2	ENST00000433375.2	c.1476G>A	p.Thr492Thr	synonymous_variant	7/7	1	NM_032575.3	ENSP00000395547.1
GLIS2	ENST00000262366.7	c.1476G>A	p.Thr492Thr	synonymous_variant	8/8	2		ENSP00000262366.3
PAM16	ENST00000577031.5	c.291+3495C>T		intron_variant		4		ENSP00000459113.1
ENSG00000262712	ENST00000574705.1	n.394C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.00596 AC: 906 AN: 152134 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00469 AC: 922 AN: 196642 Hom.: 3 AF XY: 0.00494 AC XY: 531 AN XY: 107460

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.000783

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00250

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00866

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00874 AC: 12518 AN: 1432602 Hom.: 75 Cov.: 34 AF XY: 0.00863 AC XY: 6130 AN XY: 710646

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00102

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.00229

Gnomad4 FIN exome AF: 0.00336

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.00750

GnomAD4 genome AF: 0.00594 AC: 905 AN: 152252 Hom.: 5 Cov.: 33 AF XY: 0.00522 AC XY: 389 AN XY: 74450

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00901 Hom.: 2

Bravo AF: 0.00526

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ENSG00000262712: BS1, BS2; GLIS2: BP4, BP7, BS1, BS2 -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Nephronophthisis 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

GLIS2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.048
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140403969; hg19: chr16-4387426;