rs200814551

Variant names:

• chr16-4336960-G-A
• rs200814551
• NM_032575.3:c.1011G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-4336960-G-A
• chr16-4336960-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032575.3(GLIS2):​c.1011G>A​(p.Pro337Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,610,730 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (17 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (54 hom.)
• Consequence: GLIS2 NM_032575.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.46
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-4336960-G-A is Benign according to our data. Variant chr16-4336960-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0558 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.1011G>A	p.Pro337Pro	synonymous	Exon 7 of 7	NP_115964.2	Q9BZE0
	GLIS2	NM_001318918.2		c.1011G>A	p.Pro337Pro	synonymous	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.1011G>A	p.Pro337Pro	synonymous	Exon 7 of 7	ENSP00000395547.1	Q9BZE0
	GLIS2	ENST00000886081.1		c.1047G>A	p.Pro349Pro	synonymous	Exon 7 of 7	ENSP00000556140.1
	GLIS2	ENST00000927239.1		c.1014G>A	p.Pro338Pro	synonymous	Exon 7 of 7	ENSP00000597298.1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152186 Hom.: 17 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0616

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00520 AC: 1253 AN: 240858 AF XY: 0.00470

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000838

Gnomad OTH exome AF: 0.00153

GnomAD4 exome AF: 0.00152 AC: 2220 AN: 1458426 Hom.: 54 Cov.: 35 AF XY: 0.00149 AC XY: 1081 AN XY: 725480

African (AFR) AF: 0.000150 AC: 5 AN: 33434

American (AMR) AF: 0.000202 AC: 9 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.0470 AC: 1859 AN: 39584

South Asian (SAS) AF: 0.00138 AC: 119 AN: 86058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51472

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111324

Other (OTH) AF: 0.00299 AC: 180 AN: 60216

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152304 Hom.: 17 Cov.: 34 AF XY: 0.00279 AC XY: 208 AN XY: 74470

African (AFR) AF: 0.000168 AC: 7 AN: 41570

American (AMR) AF: 0.000914 AC: 14 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0613 AC: 317 AN: 5168

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000513 Hom.: 2

Bravo AF: 0.00233

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.84
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
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: rs200814551; hg19: chr16-4386961; COSMIC: COSV52109772; COSMIC: COSV52109772;