chr16-4332270-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032575.3(GLIS2):c.-11G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,610,762 control chromosomes in the GnomAD database, including 1,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 681 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 625 hom. )

Consequence

GLIS2
NM_032575.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.508

Publications

2 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:

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 16-4332270-G-A is Benign according to our data. Variant chr16-4332270-G-A is described in ClinVar as Benign. ClinVar VariationId is 262084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS2	NM_032575.3 link	c.-11G>A		5_prime_UTR_variant	Exon 2 of 7	ENST00000433375.2	NP_115964.2	Q9BZE0
GLIS2	NM_001318918.2 link	c.-11G>A		5_prime_UTR_variant	Exon 3 of 8		NP_001305847.1	Q9BZE0B3KTH4

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLIS2	ENST00000433375.2 link	c.-11G>A	5_prime_UTR_variant	Exon 2 of 7	1	NM_032575.3	ENSP00000395547.1	Q9BZE0
GLIS2	ENST00000262366.7 link	c.-11G>A	5_prime_UTR_variant	Exon 3 of 8	2		ENSP00000262366.3	Q9BZE0
PAM16	ENST00000577031.5 link	c.292-496C>T	intron_variant	Intron 4 of 4	4		ENSP00000459113.1	I3L1U7

Frequencies

GnomAD3 genomes

AF:

0.0521

AC:

7924

AN:

152050

Hom.:

681

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.0408

GnomAD2 exomes

AF:

0.0142

AC:

3461

AN:

243058

AF XY:

0.0107

show subpopulations

Gnomad AFR exome

AF:

0.187

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.00751

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000876

Gnomad OTH exome

AF:

0.00792

GnomAD4 exome

AF:

0.00591

AC:

8623

AN:

1458596

Hom.:

625

Cov.:

AF XY:

0.00530

AC XY:

3844

AN XY:

725422

show subpopulations

African (AFR)

AF:

0.182

AC:

6096

AN:

33420

American (AMR)

AF:

0.0121

AC:

538

AN:

44498

Ashkenazi Jewish (ASJ)

AF:

0.00791

AC:

206

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00115

AC:

AN:

85890

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51776

Middle Eastern (MID)

AF:

0.0115

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000702

AC:

780

AN:

1111304

Other (OTH)

AF:

0.0139

AC:

838

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

488

977

1465

1954

2442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.0522

AC:

7940

AN:

152166

Hom.:

681

Cov.:

AF XY:

0.0508

AC XY:

3784

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.180

AC:

7457

AN:

41442

American (AMR)

AF:

0.0189

AC:

289

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00332

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68016

Other (OTH)

AF:

0.0404

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

306

613

919

1226

1532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0370

Hom.:

Bravo

AF:

0.0598

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.68

CADD

Benign

7.3

(source)

DANN

Benign

0.88

PhyloP100

-0.51

Mutation Taster

=300/0

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