dbSNP rs749326535: PAMR1:p.Val622Phe (chr11-35432655-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001001991.3(PAMR1):c.1864G>T(p.Val622Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PAMR1
NM_001001991.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

Variant links:

Genes affected

PAMR1 (HGNC:24554): (peptidase domain containing associated with muscle regeneration 1) Predicted to enable calcium ion binding activity and serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

PAMR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAMR1	NM_001001991.3 link	c.1864G>T	p.Val622Phe	missense_variant	Exon 11 of 11	ENST00000619888.5	NP_001001991.1	Q6UXH9-1
PAMR1	NM_015430.4 link	c.1915G>T	p.Val639Phe	missense_variant	Exon 12 of 12		NP_056245.2	Q6UXH9-2
PAMR1	NM_001282675.2 link	c.1744G>T	p.Val582Phe	missense_variant	Exon 13 of 13		NP_001269604.1	Q6UXH9A0A087WXE9B7Z4A8
PAMR1	NM_001282676.2 link	c.1531G>T	p.Val511Phe	missense_variant	Exon 9 of 9		NP_001269605.1	Q6UXH9-3B7Z6E5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAMR1	ENST00000619888.5 link	c.1864G>T	p.Val622Phe	missense_variant	Exon 11 of 11	1	NM_001001991.3	ENSP00000483703.1		Q6UXH9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250792

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135558

show subpopulations

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 SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727086

show subpopulations

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1915G>T (p.V639F) alteration is located in exon 12 (coding exon 12) of the PAMR1 gene. This alteration results from a G to T substitution at nucleotide position 1915, causing the valine (V) at amino acid position 639 to be replaced by a phenylalanine (F). 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

0.15

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

.;D;.;T;.;D

Eigen

Benign

-0.039

Eigen_PC

Benign

0.013

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;T;T;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.9

.;M;.;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.9

.;.;.;.;.;D

REVEL

Pathogenic

0.66

Sift4G

Uncertain

0.0050

D;D;D;D;D;D

Polyphen

0.026

B;B;.;.;.;.

Vest4

0.40

MutPred

0.82

.;Gain of catalytic residue at V622 (P = 0.1366);.;.;.;.;

MVP

0.44

ClinPred

0.93

GERP RS

3.3

Varity_R

0.69

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over