19-46019589-C-T

Variant names:

• chr19-46019589-C-T
• rs374335177
• NM_005091.3:c.346G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005091.3(PGLYRP1):​c.346G>A​(p.Ala116Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000356 in 1,461,744 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PGLYRP1 NM_005091.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

Genes affected

PGLYRP1 (HGNC:8904): (peptidoglycan recognition protein 1) Enables peptidoglycan binding activity and peptidoglycan immune receptor activity. Involved in antimicrobial humoral immune response mediated by antimicrobial peptide; killing of cells of other organism; and response to bacterium. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

CCDC61 (HGNC:33629): (coiled-coil domain containing 61) Enables identical protein binding activity and microtubule binding activity. Involved in centriole assembly and mitotic spindle assembly. Located in centriolar satellite and ciliary basal body. Part of centriolar subdistal appendage. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGLYRP1	NM_005091.3	c.346G>A	p.Ala116Thr	missense_variant	Exon 2 of 3	ENST00000008938.5	NP_005082.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGLYRP1	ENST00000008938.5	c.346G>A	p.Ala116Thr	missense_variant	Exon 2 of 3	1	NM_005091.3	ENSP00000008938.3
CCDC61	ENST00000601763.1	n.54+1157C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461744 Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24 AN XY: 727184

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: 0.0000450

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000741 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.346G>A (p.A116T) alteration is located in exon 2 (coding exon 2) of the PGLYRP1 gene. This alteration results from a G to A substitution at nucleotide position 346, causing the alanine (A) at amino acid position 116 to be replaced by a threonine (T). 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	0.27
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0078	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.24
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.010	D
Polyphen		0.98	D
Vest4		0.37
MVP		0.39
MPC		0.78
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.19
gMVP		0.79

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: rs374335177; hg19: chr19-46522847; COSMIC: COSV50517528; COSMIC: COSV50517528;