chr16-4336813-T-A

Variant names:

• chr16-4336813-T-A
• rs669561
• NM_032575.3:c.864T>A

Variant summary

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

The NM_032575.3(GLIS2):​c.864T>A​(p.Tyr288*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y288Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GLIS2 NM_032575.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.413
• Publications: 20 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.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS2	NM_032575.3	c.864T>A	p.Tyr288*	stop_gained	Exon 7 of 7	ENST00000433375.2	NP_115964.2
GLIS2	NM_001318918.2	c.864T>A	p.Tyr288*	stop_gained	Exon 8 of 8		NP_001305847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS2	ENST00000433375.2	c.864T>A	p.Tyr288*	stop_gained	Exon 7 of 7	1	NM_032575.3	ENSP00000395547.1
GLIS2	ENST00000262366.7	c.864T>A	p.Tyr288*	stop_gained	Exon 8 of 8	2		ENSP00000262366.3
ENSG00000262712	ENST00000574705.1	n.1006A>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
PAM16	ENST00000577031.5	c.291+4107A>T		intron_variant	Intron 4 of 4	4		ENSP00000459113.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 71

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.28	N
PhyloP100		-0.41
Vest4		0.81
GERP RS		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs669561; hg19: chr16-4386814;