chr5-103003035-C-G

Variant names:

• chr5-103003035-C-G
• rs78408340
• NM_001177306.2:c.1616C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001319943.1(PAM):​c.1670C>G​(p.Ser557Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00658 in 1,492,480 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (40 hom.)
• Consequence: PAM NM_001319943.1 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.95
• Publications: 40 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017059922).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319943.1. 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.1616C>G	p.Ser539Trp	missense splice_region	Exon 17 of 26	NP_001170777.1
	PAM	NM_001319943.1		c.1670C>G	p.Ser557Trp	missense splice_region	Exon 18 of 27	NP_001306872.1
	PAM	NM_000919.4		c.1616C>G	p.Ser539Trp	missense splice_region	Exon 17 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.1616C>G	p.Ser539Trp	missense splice_region	Exon 17 of 26	ENSP00000396493.3
	PAM	ENST00000304400.12	TSL:1	c.1616C>G	p.Ser539Trp	missense splice_region	Exon 17 of 26	ENSP00000306100.8
	PAM	ENST00000455264.7	TSL:1	c.1616C>G	p.Ser539Trp	missense splice_region	Exon 17 of 25	ENSP00000403461.2

Frequencies

GnomAD3 genomes AF: 0.00417 AC: 634 AN: 152066 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00725

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00373 AC: 922 AN: 247476 AF XY: 0.00370

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.00300

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00676

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00686 AC: 9190 AN: 1340296 Hom.: 40 Cov.: 21 AF XY: 0.00662 AC XY: 4458 AN XY: 673570

African (AFR) AF: 0.00135 AC: 42 AN: 31086

American (AMR) AF: 0.00339 AC: 150 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.000197 AC: 5 AN: 25322

East Asian (EAS) AF: 0.00 AC: 0 AN: 39064

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83482

European-Finnish (FIN) AF: 0.00165 AC: 88 AN: 53224

Middle Eastern (MID) AF: 0.000541 AC: 3 AN: 5548

European-Non Finnish (NFE) AF: 0.00854 AC: 8554 AN: 1002072

Other (OTH) AF: 0.00615 AC: 346 AN: 56236

GnomAD4 genome AF: 0.00417 AC: 634 AN: 152184 Hom.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74406

African (AFR) AF: 0.00111 AC: 46 AN: 41534

American (AMR) AF: 0.00504 AC: 77 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00725 AC: 493 AN: 67996

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.00398 Hom.: 0

Bravo AF: 0.00436

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00369 AC: 448

Asia WGS AF: 0.000289 AC: 2 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.78
MPC		0.77
ClinPred		0.070	T
GERP RS		5.6
Varity_R		0.82
gMVP		0.86
Mutation Taster		=202/98	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs78408340; hg19: chr5-102338739; COSMIC: COSV99053341; COSMIC: COSV99053341;