chr5-102950766-T-C

Variant names:

• chr5-102950766-T-C
• rs747114925
• NM_001177306.2:c.851T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001177306.2(PAM):​c.851T>C​(p.Leu284Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L284R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAM NM_001177306.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

PAM (HGNC:8596): (peptidylglycine alpha-amidating monooxygenase) This gene encodes a multifunctional protein. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme includes two domains with distinct catalytic activities, a peptidylglycine alpha-hydroxylating monooxygenase (PHM) domain and a peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) domain. These catalytic domains work sequentially to catalyze the conversion of neuroendocrine peptides to active alpha-amidated products. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177306.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAM	NM_001177306.2	MANE Select	c.851T>C	p.Leu284Pro	missense	Exon 12 of 26	NP_001170777.1	P19021-1
	PAM	NM_001319943.1		c.851T>C	p.Leu284Pro	missense	Exon 12 of 27	NP_001306872.1	O43832
	PAM	NM_000919.4		c.851T>C	p.Leu284Pro	missense	Exon 12 of 26	NP_000910.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAM	ENST00000438793.8	TSL:1 MANE Select	c.851T>C	p.Leu284Pro	missense	Exon 12 of 26	ENSP00000396493.3	P19021-1
	PAM	ENST00000304400.12	TSL:1	c.851T>C	p.Leu284Pro	missense	Exon 12 of 26	ENSP00000306100.8	A0A8C8KD64
	PAM	ENST00000455264.7	TSL:1	c.851T>C	p.Leu284Pro	missense	Exon 12 of 25	ENSP00000403461.2	P19021-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250908 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.83		Loss of stability (P = 0.1695)
MVP		0.99
MPC		0.78
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.98
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs747114925; hg19: chr5-102286470;