Variant chr11-35432377-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001001991.3(PAMR1):c.2142G>T(p.Trp714Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,460,154 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: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PAMR1
NM_001001991.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95

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:

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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, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PAMR1	NM_001001991.3 linkuse as main transcript	c.2142G>T	p.Trp714Cys	missense_variant	11/11	ENST00000619888.5
PAMR1	NM_015430.4 linkuse as main transcript	c.2193G>T	p.Trp731Cys	missense_variant	12/12
PAMR1	NM_001282675.2 linkuse as main transcript	c.2022G>T	p.Trp674Cys	missense_variant	13/13
PAMR1	NM_001282676.2 linkuse as main transcript	c.1809G>T	p.Trp603Cys	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAMR1	ENST00000619888.5 linkuse as main transcript	c.2142G>T	p.Trp714Cys	missense_variant	11/11	1	NM_001001991.3	P1	Q6UXH9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250116

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135212

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1460154

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726380

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The c.2193G>T (p.W731C) 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 2193, causing the tryptophan (W) at amino acid position 731 to be replaced by a cysteine (C). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.78

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.89

MutPred

0.91

.;Loss of MoRF binding (P = 0.0047);.;.;.;

MVP

0.48

ClinPred

1.0

GERP RS

5.4

Varity_R

0.99

gMVP

0.97

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