chr11-35434706-C-T

Variant names:

• chr11-35434706-C-T
• rs753313677
• NM_001001991.3:c.1432G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001991.3(PAMR1):​c.1432G>A​(p.Gly478Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PAMR1 NM_001001991.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0490

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18073454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAMR1	NM_001001991.3	c.1432G>A	p.Gly478Ser	missense_variant	Exon 10 of 11	ENST00000619888.5	NP_001001991.1
PAMR1	NM_015430.4	c.1483G>A	p.Gly495Ser	missense_variant	Exon 11 of 12		NP_056245.2
PAMR1	NM_001282675.2	c.1312G>A	p.Gly438Ser	missense_variant	Exon 12 of 13		NP_001269604.1
PAMR1	NM_001282676.2	c.1099G>A	p.Gly367Ser	missense_variant	Exon 8 of 9		NP_001269605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAMR1	ENST00000619888.5	c.1432G>A	p.Gly478Ser	missense_variant	Exon 10 of 11	1	NM_001001991.3	ENSP00000483703.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1483G>A (p.G495S) alteration is located in exon 11 (coding exon 11) of the PAMR1 gene. This alteration results from a G to A substitution at nucleotide position 1483, causing the glycine (G) at amino acid position 495 to be replaced by a serine (S). 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	0.067
BayesDel_addAF	Benign	0.0081	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.12	.;T;.;T;.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.83	T;T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	.;L;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.41	.;.;.;.;.;N
REVEL	Benign	0.29
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.063	B;B;.;.;.;.
Vest4		0.20
MutPred		0.50		.;Gain of disorder (P = 0.0806);.;.;.;.;
MVP		0.41
ClinPred		0.27	T
GERP RS		4.4
Varity_R		0.080
gMVP		0.34

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

Other links and lift over

dbSNP: rs753313677; hg19: chr11-35456254;