rs878855164

Variant names:

• chr16-4337142-T-TGGGCCCTGGGCTGCC
• rs878855164
• NM_032575.3:c.1194_1208dupGGGCCCTGGGCTGCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_032575.3(GLIS2):​c.1194_1208dupGGGCCCTGGGCTGCC​(p.Pro403_Gly404insGlyProGlyLeuPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,385,058 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GLIS2 NM_032575.3 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0600
• Publications: 0 publications found

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]

ENSG00000262712 (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]

PAM16 Gene-Disease associations (from GenCC):

• autosomal recessive spondylometaphyseal dysplasia, Megarbane type

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_032575.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS2	NM_032575.3	c.1194_1208dupGGGCCCTGGGCTGCC	p.Pro403_Gly404insGlyProGlyLeuPro	disruptive_inframe_insertion	Exon 7 of 7	ENST00000433375.2	NP_115964.2
GLIS2	NM_001318918.2	c.1194_1208dupGGGCCCTGGGCTGCC	p.Pro403_Gly404insGlyProGlyLeuPro	disruptive_inframe_insertion	Exon 8 of 8		NP_001305847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS2	ENST00000433375.2	c.1194_1208dupGGGCCCTGGGCTGCC	p.Pro403_Gly404insGlyProGlyLeuPro	disruptive_inframe_insertion	Exon 7 of 7	1	NM_032575.3	ENSP00000395547.1
GLIS2	ENST00000262366.7	c.1194_1208dupGGGCCCTGGGCTGCC	p.Pro403_Gly404insGlyProGlyLeuPro	disruptive_inframe_insertion	Exon 8 of 8	2		ENSP00000262366.3
ENSG00000262712	ENST00000574705.1	n.662_676dupGGCAGCCCAGGGCCC		non_coding_transcript_exon_variant	Exon 1 of 1	6
PAM16	ENST00000577031.5	c.291+3763_291+3777dupGGCAGCCCAGGGCCC		intron_variant	Intron 4 of 4	4		ENSP00000459113.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1385058 Hom.: 0 Cov.: 35 AF XY: 0.00000146 AC XY: 1 AN XY: 683554

African (AFR) AF: 0.00 AC: 0 AN: 31528

American (AMR) AF: 0.00 AC: 0 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4318

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078606

Other (OTH) AF: 0.00 AC: 0 AN: 57742

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Uncertain:1

Feb 07, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this is a rare, in-frame insertion with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. While this variant is not present in population databases (ExAC), the frequency information is unreliable due to low sequence coverage of this region. This variant has not been reported in the literature in individuals with a GLIS2-related disease. This sequence change inserts 15 nucleotides in exon 6 of the GLIS2 mRNA (c.1194_1208dupGGGCCCTGGGCTGCC). This leads to the insertion of 5 amino acid residues in the GLIS2 protein (p.Gly401_Pro405dup) but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.060

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878855164; hg19: chr16-4387143;