Genetic Variant NM_173543.3:c.273G>C (chr3-138103699-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_173543.3(DZIP1L):c.273G>C(p.Gln91His) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DZIP1L
NM_173543.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.38

Publications

5 publications found

Variant links:

Genes affected

DZIP1L (HGNC:26551): (DAZ interacting zinc finger protein 1 like) Predicted to enable metal ion binding activity. Involved in cilium assembly and regulation of protein localization. Located in ciliary basal body. Colocalizes with centriole. Implicated in polycystic kidney disease 5. [provided by Alliance of Genome Resources, Apr 2022]

DZIP1L Gene-Disease associations (from GenCC):

autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
polycystic kidney disease 5
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

DZIP1L links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

PP5

Variant 3-138103699-C-G is Pathogenic according to our data. Variant chr3-138103699-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 431432.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DZIP1L	NM_173543.3 link	c.273G>C	p.Gln91His	missense_variant	Exon 2 of 16	ENST00000327532.7	NP_775814.2	Q8IYY4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DZIP1L	ENST00000327532.7 link	c.273G>C	p.Gln91His	missense_variant	Exon 2 of 16	1	NM_173543.3	ENSP00000332148.2		Q8IYY4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460140

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726452

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111904

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Polycystic kidney disease 5

Pathogenic:1

Aug 07, 2017

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

4.4

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.62

Gain of methylation at R88 (P = 0.151);Gain of methylation at R88 (P = 0.151);

MVP

0.42

MPC

0.43

ClinPred

1.0

GERP RS

4.8

Varity_R

0.76

gMVP

0.77

Mutation Taster

=15/85

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over