rs200720013

Positions:

• chr16-4337054-G-A
• chr16-4337054-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_032575.3(GLIS2):​c.1105G>A​(p.Gly369Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,569,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: GLIS2 NM_032575.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.54

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0073821843).
• BP6: Variant 16-4337054-G-A is Benign according to our data. Variant chr16-4337054-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216802.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS2	NM_032575.3	c.1105G>A	p.Gly369Ser	missense_variant	7/7	ENST00000433375.2
GLIS2	NM_001318918.2	c.1105G>A	p.Gly369Ser	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS2	ENST00000433375.2	c.1105G>A	p.Gly369Ser	missense_variant	7/7	1	NM_032575.3	P1
	ENST00000574705.1	n.765C>T		non_coding_transcript_exon_variant	1/1
GLIS2	ENST00000262366.7	c.1105G>A	p.Gly369Ser	missense_variant	8/8	2		P1
PAM16	ENST00000577031.5	c.291+3866C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152166 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000937 AC: 162 AN: 172802 Hom.: 0 AF XY: 0.000763 AC XY: 73 AN XY: 95710

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.000311

Gnomad ASJ exome AF: 0.00613

Gnomad EAS exome AF: 0.00569

Gnomad SAS exome AF: 0.0000403

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.000441 AC: 625 AN: 1416938 Hom.: 0 Cov.: 35 AF XY: 0.000431 AC XY: 303 AN XY: 702296

Gnomad4 AFR exome AF: 0.0000618

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00793

Gnomad4 EAS exome AF: 0.00276

Gnomad4 SAS exome AF: 0.0000857

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.000730

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152284 Hom.: 1 Cov.: 34 AF XY: 0.000551 AC XY: 41 AN XY: 74456

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.000684

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000605 AC: 5

ExAC AF: 0.000541 AC: 62

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nephronophthisis 7 Uncertain:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.80
DEOGEN2	Benign	0.095	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.48	N;N
REVEL	Benign	0.14
Sift	Benign	0.23	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.019	B;B
Vest4		0.16
MVP		0.14
MPC		0.28
ClinPred		0.040	T
GERP RS		6.0
Varity_R		0.12
gMVP		0.50

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: rs200720013; hg19: chr16-4387055;