16-58280751-G-C

Variant names:

• chr16-58280751-G-C
• rs1964703629
• NM_001305173.2:c.661C>G

Variant summary

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

The NM_001305173.2(PRSS54):​c.661C>G​(p.Pro221Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000829 in 1,448,054 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: 0.0000083 (0 hom.)
• Consequence: PRSS54 NM_001305173.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

Genes affected

PRSS54 (HGNC:26336): (serine protease 54) This gene encodes a putative serine-type endopeptidase containing the peptidase S1 domain. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2015]

CFAP263 (HGNC:25002): (cilia and flagella associated protein 263) Involved in cilium assembly. Located in centriolar satellite and ciliary basal body. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
PRSS54	NM_001305173.2	c.661C>G	p.Pro221Ala	missense_variant	Exon 7 of 7	ENST00000567164.6	NP_001292102.1
CFAP263	NM_014157.4	c.*974G>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000219299.8	NP_054876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS54	ENST00000567164.6	c.661C>G	p.Pro221Ala	missense_variant	Exon 7 of 7	1	NM_001305173.2	ENSP00000455024.1
CCDC113	ENST00000219299.8	c.*974G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_014157.4	ENSP00000219299.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000829 AC: 12 AN: 1448054 Hom.: 0 Cov.: 32 AF XY: 0.00000836 AC XY: 6 AN XY: 717930

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: 0.0000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.661C>G (p.P221A) alteration is located in exon 7 (coding exon 5) of the PRSS54 gene. This alteration results from a C to G substitution at nucleotide position 661, causing the proline (P) at amino acid position 221 to be replaced by an alanine (A). 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	0.091
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.67	.;T;T;T
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.6	L;L;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.026	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.17
MutPred		0.61		Loss of glycosylation at P221 (P = 0.0751);Loss of glycosylation at P221 (P = 0.0751);.;.;
MVP		0.85
MPC		0.44
ClinPred		0.81	D
GERP RS		3.8
Varity_R		0.27
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs1964703629; hg19: chr16-58314655;