Genetic Variant CUZD1:p.Pro472Ser (chr10-122833909-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022034.6(CUZD1):c.1414C>T(p.Pro472Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CUZD1
NM_022034.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.973

Variant links:

Genes affected

CUZD1 (HGNC:17937): (CUB and zona pellucida like domains 1) Predicted to be involved in trypsinogen activation. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

CUZD1 links:

ENSG00000286088 (HGNC:):

ENSG00000286088 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34820747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUZD1	NM_022034.6 link	c.1414C>T	p.Pro472Ser	missense_variant	Exon 8 of 9	ENST00000392790.6	NP_071317.2	Q86UP6-1
CUZD1	NR_037912.2 link	n.1277C>T		non_coding_transcript_exon_variant	Exon 7 of 8
FAM24B-CUZD1	NR_037915.1 link	n.2090C>T		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CUZD1	ENST00000392790.6 link	c.1414C>T	p.Pro472Ser	missense_variant	Exon 8 of 9	1	NM_022034.6	ENSP00000376540.1	Q86UP6-1
ENSG00000286088	ENST00000368904.6 link	n.*575C>T		non_coding_transcript_exon_variant	Exon 9 of 10	1		ENSP00000357900.2	A0A499FIG0
ENSG00000286088	ENST00000368904.6 link	n.*575C>T		3_prime_UTR_variant	Exon 9 of 10	1		ENSP00000357900.2	A0A499FIG0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461282

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726924

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1414C>T (p.P472S) alteration is located in exon 8 (coding exon 8) of the CUZD1 gene. This alteration results from a C to T substitution at nucleotide position 1414, causing the proline (P) at amino acid position 472 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.68

.;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.35

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.4

L;L

PROVEAN

Benign

-0.73

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.28

T;T

Sift4G

Benign

0.15

T;T

Polyphen

1.0

D;D

Vest4

0.29

MutPred

0.50

Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);

MVP

0.79

MPC

0.39

ClinPred

0.85

GERP RS

4.4

Varity_R

0.066

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over