rs72766563

Variant names:

• chr16-4333397-G-T
• rs72766563
• NM_032575.3:c.223G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032575.3(GLIS2):​c.223G>T​(p.Ala75Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 1,613,012 control chromosomes in the GnomAD database, including 536 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (43 hom., cov: 32)
  • Exomes 𝑓: 0.024 (493 hom.)
• Consequence: GLIS2 NM_032575.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.395
• Publications: 5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.002263397).
• BP6: Variant 16-4333397-G-T is Benign according to our data. Variant chr16-4333397-G-T is described in ClinVar as Benign. ClinVar VariationId is 262085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0176 (2679/152196) while in subpopulation NFE AF = 0.0254 (1725/67994). AF 95% confidence interval is 0.0244. There are 43 homozygotes in GnomAd4. There are 1337 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS2	NM_032575.3	MANE Select	c.223G>T	p.Ala75Ser	missense	Exon 3 of 7	NP_115964.2
	GLIS2	NM_001318918.2		c.223G>T	p.Ala75Ser	missense	Exon 4 of 8	NP_001305847.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS2	ENST00000433375.2	TSL:1 MANE Select	c.223G>T	p.Ala75Ser	missense	Exon 3 of 7	ENSP00000395547.1
	GLIS2	ENST00000262366.7	TSL:2	c.223G>T	p.Ala75Ser	missense	Exon 4 of 8	ENSP00000262366.3
	PAM16	ENST00000577031.5	TSL:4	c.292-1623C>A		intron	N/A	ENSP00000459113.1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2678 AN: 152078 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0582

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0186 AC: 4648 AN: 249892 AF XY: 0.0186

Gnomad AFR exome AF: 0.00391

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0590

Gnomad NFE exome AF: 0.0259

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0238 AC: 34738 AN: 1460816 Hom.: 493 Cov.: 32 AF XY: 0.0233 AC XY: 16925 AN XY: 726742

African (AFR) AF: 0.00355 AC: 119 AN: 33480

American (AMR) AF: 0.00353 AC: 158 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26136

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

South Asian (SAS) AF: 0.00509 AC: 439 AN: 86256

European-Finnish (FIN) AF: 0.0557 AC: 2919 AN: 52392

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0269 AC: 29965 AN: 1111990

Other (OTH) AF: 0.0174 AC: 1053 AN: 60374

GnomAD4 genome AF: 0.0176 AC: 2679 AN: 152196 Hom.: 43 Cov.: 32 AF XY: 0.0180 AC XY: 1337 AN XY: 74424

African (AFR) AF: 0.00494 AC: 205 AN: 41522

American (AMR) AF: 0.00458 AC: 70 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4822

European-Finnish (FIN) AF: 0.0582 AC: 617 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0254 AC: 1725 AN: 67994

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0211 Hom.: 150

Bravo AF: 0.0131

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00592 AC: 26

ESP6500EA AF: 0.0246 AC: 211

ExAC AF: 0.0186 AC: 2261

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0199

EpiControl AF: 0.0201

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.3
DANN	Benign	0.95
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.099	N
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.40
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.018
Sift	Benign	0.33	T
Sift4G	Benign	0.80	T
Polyphen		0.0030	B
Vest4		0.081
MPC		0.26
ClinPred		0.0010	T
GERP RS		0.55
Varity_R		0.025
gMVP		0.17
Mutation Taster		=100/0	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: rs72766563; hg19: chr16-4383398; COSMIC: COSV52110789; COSMIC: COSV52110789;