rs8057701

Variant names:

• chr16-4337423-A-G
• rs8057701
• NM_032575.3:c.1474A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032575.3(GLIS2):​c.1474A>G​(p.Thr492Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 1,584,644 control chromosomes in the GnomAD database, including 1,809 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T492M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.062 (437 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1372 hom.)
• Consequence: GLIS2 NM_032575.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.977
• Publications: 15 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ENSG00000262712 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018239915).
• BP6: Variant 16-4337423-A-G is Benign according to our data. Variant chr16-4337423-A-G is described in ClinVar as Benign. ClinVar VariationId is 167149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

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.1474A>G	p.Thr492Ala	missense	Exon 7 of 7	NP_115964.2	Q9BZE0
	GLIS2	NM_001318918.2		c.1474A>G	p.Thr492Ala	missense	Exon 8 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.1474A>G	p.Thr492Ala	missense	Exon 7 of 7	ENSP00000395547.1	Q9BZE0
	GLIS2	ENST00000886081.1		c.1510A>G	p.Thr504Ala	missense	Exon 7 of 7	ENSP00000556140.1
	GLIS2	ENST00000927239.1		c.1477A>G	p.Thr493Ala	missense	Exon 7 of 7	ENSP00000597298.1

Frequencies

GnomAD3 genomes AF: 0.0615 AC: 9351 AN: 152026 Hom.: 433 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0462

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0386

Gnomad OTH AF: 0.0575

GnomAD2 exomes AF: 0.0335 AC: 6581 AN: 196554 AF XY: 0.0315

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0296

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.0000648

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0360

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0374 AC: 53622 AN: 1432500 Hom.: 1372 Cov.: 34 AF XY: 0.0364 AC XY: 25866 AN XY: 710542

African (AFR) AF: 0.145 AC: 4785 AN: 33008

American (AMR) AF: 0.0327 AC: 1364 AN: 41752

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 785 AN: 25520

East Asian (EAS) AF: 0.000156 AC: 6 AN: 38476

South Asian (SAS) AF: 0.0138 AC: 1141 AN: 82388

European-Finnish (FIN) AF: 0.0203 AC: 951 AN: 46832

Middle Eastern (MID) AF: 0.0471 AC: 270 AN: 5730

European-Non Finnish (NFE) AF: 0.0381 AC: 41907 AN: 1099454

Other (OTH) AF: 0.0407 AC: 2413 AN: 59340

GnomAD4 genome AF: 0.0617 AC: 9386 AN: 152144 Hom.: 437 Cov.: 33 AF XY: 0.0598 AC XY: 4451 AN XY: 74394

African (AFR) AF: 0.131 AC: 5451 AN: 41474

American (AMR) AF: 0.0461 AC: 705 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 140 AN: 3468

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5160

South Asian (SAS) AF: 0.0128 AC: 62 AN: 4826

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10620

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0386 AC: 2624 AN: 67990

Other (OTH) AF: 0.0569 AC: 120 AN: 2108

Alfa AF: 0.0456 Hom.: 285

Bravo AF: 0.0677

TwinsUK AF: 0.0369 AC: 137

ALSPAC AF: 0.0446 AC: 172

ESP6500AA AF: 0.122 AC: 527

ESP6500EA AF: 0.0314 AC: 268

ExAC AF: 0.0280 AC: 3324

Asia WGS AF: 0.0200 AC: 68 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.66	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.98
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.070
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.17	T
Polyphen		0.37	B
Vest4		0.030
MPC		0.28
ClinPred		0.024	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.51
Mutation Taster		=80/20	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8057701; hg19: chr16-4387424; COSMIC: COSV52110973; COSMIC: COSV52110973;