10-122834971-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022034.6(CUZD1):c.1117G>A(p.Val373Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CUZD1 NM_022034.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0130

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUZD1	NM_022034.6	c.1117G>A	p.Val373Met	missense_variant	7/9	ENST00000392790.6
FAM24B-CUZD1	NR_037915.1	n.1793G>A		non_coding_transcript_exon_variant	9/11
CUZD1	NR_037912.2	n.980G>A		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUZD1	ENST00000392790.6	c.1117G>A	p.Val373Met	missense_variant	7/9	1	NM_022034.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461552 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727064

Gnomad4 AFR exome AF: 0.0000299

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.: 32

Bravo AF: 0.00000756

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

Jun 06, 2023

The c.1117G>A (p.V373M) alteration is located in exon 7 (coding exon 7) of the CUZD1 gene. This alteration results from a G to A substitution at nucleotide position 1117, causing the valine (V) at amino acid position 373 to be replaced by a methionine (M). 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	0.090
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D
Eigen	Benign	-0.011
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.066	N
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	-0.035	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	0.95	N;N;N;N;N;N;N
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.041	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.98	D;D
Vest4		0.12
MutPred		0.81		Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);
MVP		0.84
MPC		0.14
ClinPred		0.87	D
GERP RS		2.9
Varity_R		0.050
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs780999461; hg19: chr10-124594487;