NM_001177306.2:c.898C>T

Variant names:

• chr5-102950813-C-T
• NM_001177306.2:c.898C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001177306.2(PAM):​c.898C>T​(p.His300Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAM NM_001177306.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10435712).

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.898C>T	p.His300Tyr	missense	Exon 12 of 26	NP_001170777.1	P19021-1
	PAM	NM_001319943.1		c.898C>T	p.His300Tyr	missense	Exon 12 of 27	NP_001306872.1	O43832
	PAM	NM_000919.4		c.898C>T	p.His300Tyr	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.898C>T	p.His300Tyr	missense	Exon 12 of 26	ENSP00000396493.3	P19021-1
	PAM	ENST00000304400.12	TSL:1	c.898C>T	p.His300Tyr	missense	Exon 12 of 26	ENSP00000306100.8	A0A8C8KD64
	PAM	ENST00000455264.7	TSL:1	c.898C>T	p.His300Tyr	missense	Exon 12 of 25	ENSP00000403461.2	P19021-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.038
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-1.2	N
PhyloP100		2.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.074
Sift	Benign	0.59	T
Sift4G	Benign	0.98	T
Polyphen		0.0010	B
Vest4		0.31
MutPred		0.65		Gain of sheet (P = 0.039)
MVP		0.56
MPC		0.29
ClinPred		0.30	T
GERP RS		5.5
Varity_R		0.042
gMVP		0.71
Mutation Taster		=82/18	polymorphism

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

hg19: chr5-102286517;