rs72766563

chr16-4333397-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032575.3(GLIS2):c.223G>T(p.Ala75Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 1,613,012 control chromosomes in the GnomAD database, including 536 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (43 hom., cov: 32)
  • Exomes 𝑓: 0.024 (493 hom.)
• Consequence: GLIS2 NM_032575.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.395

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002263397).
• BP6: Variant 16-4333397-G-T is Benign according to our data. Variant chr16-4333397-G-T is described in ClinVar as [Benign]. Clinvar id is 262085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-4333397-G-T is described in Lovd as [Benign]. Variant chr16-4333397-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0176 (2679/152196) while in subpopulation NFE AF= 0.0254 (1725/67994). AF 95% confidence interval is 0.0244. There are 43 homozygotes in gnomad4. There are 1337 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS2	NM_032575.3	c.223G>T	p.Ala75Ser	missense_variant	3/7	ENST00000433375.2
GLIS2	NM_001318918.2	c.223G>T	p.Ala75Ser	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS2	ENST00000433375.2	c.223G>T	p.Ala75Ser	missense_variant	3/7	1	NM_032575.3	P1
GLIS2	ENST00000262366.7	c.223G>T	p.Ala75Ser	missense_variant	4/8	2		P1
PAM16	ENST00000577031.5	c.292-1623C>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2678 AN: 152078 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0582

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0186 AC: 4648 AN: 249892 Hom.: 80 AF XY: 0.0186 AC XY: 2525 AN XY: 135612

Gnomad AFR exome AF: 0.00391

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00546

Gnomad FIN exome AF: 0.0590

Gnomad NFE exome AF: 0.0259

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0238 AC: 34738 AN: 1460816 Hom.: 493 Cov.: 32 AF XY: 0.0233 AC XY: 16925 AN XY: 726742

Gnomad4 AFR exome AF: 0.00355

Gnomad4 AMR exome AF: 0.00353

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00509

Gnomad4 FIN exome AF: 0.0557

Gnomad4 NFE exome AF: 0.0269

Gnomad4 OTH exome AF: 0.0174

GnomAD4 genome AF: 0.0176 AC: 2679 AN: 152196 Hom.: 43 Cov.: 32 AF XY: 0.0180 AC XY: 1337 AN XY: 74424

Gnomad4 AFR AF: 0.00494

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0582

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0213 Hom.: 67

Bravo AF: 0.0131

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00592 AC: 26

ESP6500EA AF: 0.0246 AC: 211

ExAC AF: 0.0186 AC: 2261

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0199

EpiControl AF: 0.0201

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Nephronophthisis 7 Benign:1

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 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	0.098
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	5.3
Dann	Benign	0.95
DEOGEN2	Benign	0.061	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.099	N
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.018
Sift	Benign	0.33	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.0030	B;B
Vest4		0.081
MPC		0.26
ClinPred		0.0010	T
GERP RS		0.55
Varity_R		0.025
gMVP		0.17

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: rs72766563; hg19: chr16-4383398; COSMIC: COSV52110789; COSMIC: COSV52110789;