16-4337260-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_032575.3(GLIS2):c.1311A>C(p.Ala437Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,548,916 control chromosomes in the GnomAD database, including 25,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 8723 hom., cov: 34)

Exomes 𝑓: 0.14 ( 17187 hom. )

Consequence

GLIS2
NM_032575.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.578

Publications

5 publications found

Variant links:

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]

GLIS2 links:

ENSG00000262712 (HGNC:):

ENSG00000262712 links:

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

PAM16 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 16-4337260-A-C is Benign according to our data. Variant chr16-4337260-A-C is described in ClinVar as Benign. ClinVar VariationId is 96223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.578 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS2	NM_032575.3 link	c.1311A>C	p.Ala437Ala	synonymous_variant	Exon 7 of 7	ENST00000433375.2	NP_115964.2	Q9BZE0
GLIS2	NM_001318918.2 link	c.1311A>C	p.Ala437Ala	synonymous_variant	Exon 8 of 8		NP_001305847.1	Q9BZE0B3KTH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLIS2	ENST00000433375.2 link	c.1311A>C	p.Ala437Ala	synonymous_variant	Exon 7 of 7	1	NM_032575.3	ENSP00000395547.1	Q9BZE0
GLIS2	ENST00000262366.7 link	c.1311A>C	p.Ala437Ala	synonymous_variant	Exon 8 of 8	2		ENSP00000262366.3	Q9BZE0
ENSG00000262712	ENST00000574705.1 link	n.559T>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
PAM16	ENST00000577031.5 link	c.291+3660T>G		intron_variant	Intron 4 of 4	4		ENSP00000459113.1	I3L1U7

Frequencies

GnomAD3 genomes

AF:

0.267

AC:

40545

AN:

152032

Hom.:

8688

Cov.:

show subpopulations

Gnomad AFR

AF:

0.594

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.244

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.243

GnomAD2 exomes

AF:

0.169

AC:

24801

AN:

146618

AF XY:

0.161

show subpopulations

Gnomad AFR exome

AF:

0.606

Gnomad AMR exome

AF:

0.219

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.108

Gnomad FIN exome

AF:

0.135

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.151

GnomAD4 exome

AF:

0.136

AC:

189485

AN:

1396766

Hom.:

17187

Cov.:

AF XY:

0.135

AC XY:

92841

AN XY:

689258

show subpopulations

African (AFR)

AF:

0.605

AC:

19129

AN:

31628

American (AMR)

AF:

0.230

AC:

8250

AN:

35868

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

3859

AN:

25178

East Asian (EAS)

AF:

0.105

AC:

3760

AN:

35826

South Asian (SAS)

AF:

0.148

AC:

11749

AN:

79354

European-Finnish (FIN)

AF:

0.134

AC:

6100

AN:

45580

Middle Eastern (MID)

AF:

0.179

AC:

1005

AN:

5600

European-Non Finnish (NFE)

AF:

0.117

AC:

126048

AN:

1079724

Other (OTH)

AF:

0.165

AC:

9585

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

11823

23647

35470

47294

59117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4844

9688

14532

19376

24220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.267

AC:

40633

AN:

152150

Hom.:

8723

Cov.:

AF XY:

0.265

AC XY:

19730

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.594

AC:

24644

AN:

41488

American (AMR)

AF:

0.244

AC:

3734

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

567

AN:

3470

East Asian (EAS)

AF:

0.102

AC:

525

AN:

5168

South Asian (SAS)

AF:

0.161

AC:

776

AN:

4830

European-Finnish (FIN)

AF:

0.147

AC:

1553

AN:

10594

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.120

AC:

8175

AN:

67976

Other (OTH)

AF:

0.242

AC:

511

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1241

2482

3723

4964

6205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.127

Hom.:

633

Bravo

AF:

0.289

Asia WGS

AF:

0.191

AC:

666

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 05, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nephronophthisis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis 7

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.0

(source)

DANN

Benign

0.63

PhyloP100

-0.58

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over