16-4334870-G-T

Variant names:

• chr16-4334870-G-T
• rs147175353
• NM_032575.3:c.415G>T
• GLIS2 p.Gly139Trp

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032575.3(GLIS2):​c.415G>T​(p.Gly139Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,460,622 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G139R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GLIS2 NM_032575.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88
• 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]

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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032575.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS2	NM_032575.3	MANE Select	c.415G>T	p.Gly139Trp	missense	Exon 4 of 7	NP_115964.2	Q9BZE0
	GLIS2	NM_001318918.2		c.415G>T	p.Gly139Trp	missense	Exon 5 of 8	NP_001305847.1	Q9BZE0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS2	ENST00000433375.2	TSL:1 MANE Select	c.415G>T	p.Gly139Trp	missense	Exon 4 of 7	ENSP00000395547.1	Q9BZE0
	GLIS2	ENST00000886081.1		c.415G>T	p.Gly139Trp	missense	Exon 4 of 7	ENSP00000556140.1
	GLIS2	ENST00000927239.1		c.415G>T	p.Gly139Trp	missense	Exon 4 of 7	ENSP00000597298.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460622 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726610

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.25
gMVP		0.38
Mutation Taster		=67/33	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs147175353;

hg19: chr16-4384871;