rs34543395

Variant names:

• chr16-4332350-C-A
• rs34543395
• NM_032575.3:c.70C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-4332350-C-A
• chr16-4332350-C-G
• chr16-4332350-C-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_032575.3(GLIS2):​c.70C>A​(p.Arg24Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,142 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (14 hom., cov: 32)
  • Exomes 𝑓: 0.011 (102 hom.)
• Consequence: GLIS2 NM_032575.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.927
• Publications: 2 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 16-4332350-C-A is Benign according to our data. Variant chr16-4332350-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.927 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 14 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.70C>A	p.Arg24Arg	synonymous	Exon 2 of 7	NP_115964.2
	GLIS2	NM_001318918.2		c.70C>A	p.Arg24Arg	synonymous	Exon 3 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.70C>A	p.Arg24Arg	synonymous	Exon 2 of 7	ENSP00000395547.1
	GLIS2	ENST00000262366.7	TSL:2	c.70C>A	p.Arg24Arg	synonymous	Exon 3 of 8	ENSP00000262366.3
	PAM16	ENST00000577031.5	TSL:4	c.292-576G>T		intron	N/A	ENSP00000459113.1

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1243 AN: 152212 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00656 AC: 1634 AN: 248986 AF XY: 0.00653

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00365

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00560

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00773

GnomAD4 exome AF: 0.0114 AC: 16600 AN: 1460812 Hom.: 102 Cov.: 32 AF XY: 0.0108 AC XY: 7869 AN XY: 726708

African (AFR) AF: 0.00140 AC: 47 AN: 33480

American (AMR) AF: 0.00338 AC: 151 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00155 AC: 134 AN: 86254

European-Finnish (FIN) AF: 0.00637 AC: 334 AN: 52402

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

European-Non Finnish (NFE) AF: 0.0137 AC: 15213 AN: 1111982

Other (OTH) AF: 0.0110 AC: 667 AN: 60378

GnomAD4 genome AF: 0.00816 AC: 1243 AN: 152330 Hom.: 14 Cov.: 32 AF XY: 0.00796 AC XY: 593 AN XY: 74486

African (AFR) AF: 0.00236 AC: 98 AN: 41582

American (AMR) AF: 0.00660 AC: 101 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00574 AC: 61 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0129 AC: 880 AN: 68022

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00729 Hom.: 3

Bravo AF: 0.00791

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.00984

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.0
DANN	Benign	0.83
PhyloP100		0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs34543395; hg19: chr16-4382351;