10-122836347-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022034.6(CUZD1):c.821C>A(p.Ser274Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,333,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: CUZD1 NM_022034.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.70

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]

FAM24B-CUZD1 (HGNC:):

ACMG classification

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=0.39097401).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUZD1	NM_022034.6	c.821C>A	p.Ser274Tyr	missense_variant	6/9	ENST00000392790.6
FAM24B-CUZD1	NR_037915.1	n.1497C>A		non_coding_transcript_exon_variant	8/11
CUZD1	NR_037912.2	n.684C>A		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUZD1	ENST00000392790.6	c.821C>A	p.Ser274Tyr	missense_variant	6/9	1	NM_022034.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000375 AC: 5 AN: 1333386 Hom.: 0 Cov.: 30 AF XY: 0.00000606 AC XY: 4 AN XY: 659636

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: 0.0000440

Gnomad4 FIN exome AF: 0.0000209

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000184

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.821C>A (p.S274Y) alteration is located in exon 6 (coding exon 6) of the CUZD1 gene. This alteration results from a C to A substitution at nucleotide position 821, causing the serine (S) at amino acid position 274 to be replaced by a tyrosine (Y). 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	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.24
MVP		0.75
MPC		0.43
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.48
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs777085460; hg19: chr10-124595863;