rs147175353

chr16-4334870-G-Achr16-4334870-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_032575.3(GLIS2):c.415G>A(p.Gly139Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00059 in 1,612,616 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: GLIS2 NM_032575.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.88

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007631421).
• BP6: Variant 16-4334870-G-A is Benign according to our data. Variant chr16-4334870-G-A is described in ClinVar as [Benign]. Clinvar id is 241705.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS2	NM_032575.3	c.415G>A	p.Gly139Arg	missense_variant	4/7	ENST00000433375.2
GLIS2	NM_001318918.2	c.415G>A	p.Gly139Arg	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS2	ENST00000433375.2	c.415G>A	p.Gly139Arg	missense_variant	4/7	1	NM_032575.3	P1
GLIS2	ENST00000262366.7	c.415G>A	p.Gly139Arg	missense_variant	5/8	2		P1
PAM16	ENST00000577031.5	c.292-3096C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 423 AN: 151876 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00951

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000861 AC: 215 AN: 249630 Hom.: 0 AF XY: 0.000561 AC XY: 76 AN XY: 135476

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000359 AC: 524 AN: 1460622 Hom.: 2 Cov.: 32 AF XY: 0.000314 AC XY: 228 AN XY: 726610

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00281 AC: 427 AN: 151994 Hom.: 0 Cov.: 32 AF XY: 0.00253 AC XY: 188 AN XY: 74298

Gnomad4 AFR AF: 0.00958

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000259 Hom.: 0

Bravo AF: 0.00329

ESP6500AA AF: 0.00910 AC: 40

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00101 AC: 123

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.26
Sift	Benign	0.12	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.51	P;P
Vest4		0.46
MutPred		0.40		Loss of glycosylation at S138 (P = 0.0461);Loss of glycosylation at S138 (P = 0.0461);
MVP		0.46
MPC		0.45
ClinPred		0.021	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.12
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs147175353; hg19: chr16-4384871; COSMIC: COSV52111475; COSMIC: COSV52111475;