Genetic Variant PRAM1:p.Gly603Arg (chr19-8490693-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_032152.5(PRAM1):c.1807G>C(p.Gly603Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000995 in 1,607,298 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

PRAM1
NM_032152.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.86

Variant links:

Genes affected

PRAM1 (HGNC:30091): (PML-RARA regulated adaptor molecule 1) The protein encoded by this gene is similar to FYN binding protein (FYB/SLAP-130), an adaptor protein involved in T cell receptor mediated signaling. This gene is expressed and regulated during normal myelopoiesis. The expression of this gene is induced by retinoic acid and is inhibited by the expression of PML-RARalpha, a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RARalpha). [provided by RefSeq, Jul 2008]

PRAM1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAM1	NM_032152.5 link	c.1807G>C	p.Gly603Arg	missense_variant	Exon 7 of 10	ENST00000423345.5	NP_115528.4	Q96QH2
PRAM1	XM_011528352.3 link	c.1813G>C	p.Gly605Arg	missense_variant	Exon 7 of 9		XP_011526654.1
PRAM1	XM_005272502.3 link	c.1807G>C	p.Gly603Arg	missense_variant	Exon 7 of 9		XP_005272559.1
PRAM1	XM_011528353.3 link	c.1813G>C	p.Gly605Arg	missense_variant	Exon 7 of 10		XP_011526655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRAM1	ENST00000423345.5 link	c.1807G>C	p.Gly603Arg	missense_variant	Exon 7 of 10	1	NM_032152.5	ENSP00000408342.2	Q96QH2
PRAM1	ENST00000594696.1 link	n.1097G>C		non_coding_transcript_exon_variant	Exon 3 of 6	5
PRAM1	ENST00000599698.5 link	n.183G>C		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

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

GnomAD3 exomes

AF:

0.0000169

AC:

AN:

237280

Hom.:

AF XY:

0.00000775

AC XY:

AN XY:

128994

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000204

Gnomad EAS exome

AF:

0.000117

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1455140

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

723378

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000269

Gnomad4 EAS exome

AF:

0.000178

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000252

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000248

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.18

Sift

Benign

0.045

Sift4G

Benign

0.087

Vest4

0.61

MVP

0.58

MPC

0.63

ClinPred

0.88

GERP RS

5.2

Varity_R

0.32

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over