chr11-35434597-A-G

Variant names:

• chr11-35434597-A-G
• rs998121452
• NM_001001991.3:c.1541T>C

Variant summary

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

The NM_001001991.3(PAMR1):​c.1541T>C​(p.Met514Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M514V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: PAMR1 NM_001001991.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61
• Publications: 0 publications found

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]

SLC1A2-AS2 (HGNC:40535): (SLC1A2 antisense RNA 2)

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=0.20754963).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001991.3. 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
	PAMR1	NM_001001991.3	MANE Select	c.1541T>C	p.Met514Thr	missense	Exon 10 of 11	NP_001001991.1	Q6UXH9-1
	PAMR1	NM_015430.4		c.1592T>C	p.Met531Thr	missense	Exon 11 of 12	NP_056245.2	Q6UXH9-2
	PAMR1	NM_001282675.2		c.1421T>C	p.Met474Thr	missense	Exon 12 of 13	NP_001269604.1	A0A087WXE9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAMR1	ENST00000619888.5	TSL:1 MANE Select	c.1541T>C	p.Met514Thr	missense	Exon 10 of 11	ENSP00000483703.1	Q6UXH9-1
	PAMR1	ENST00000622144.4	TSL:1	c.1592T>C	p.Met531Thr	missense	Exon 11 of 12	ENSP00000482899.1	Q6UXH9-2
	PAMR1	ENST00000953162.1		c.1562T>C	p.Met521Thr	missense	Exon 10 of 11	ENSP00000623221.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251460 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152034 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74242

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.0000656 AC: 1 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000329 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.10
BayesDel_addAF	Benign	-0.0089	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	-0.035	N
PhyloP100		4.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.29	N
REVEL	Uncertain	0.33
Sift4G	Benign	0.33	T
Polyphen		0.018	B
Vest4		0.25
MVP		0.44
ClinPred		0.87	D
GERP RS		5.4
Varity_R		0.35
gMVP		0.29
Mutation Taster		=76/24	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

dbSNP: rs998121452; hg19: chr11-35456145;