19-8490494-C-T

Variant names:

• chr19-8490494-C-T
• rs1295870494
• NM_032152.5:c.1922G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032152.5(PRAM1):​c.1922G>A​(p.Arg641Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,096 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRAM1 NM_032152.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAM1	NM_032152.5	c.1922G>A	p.Arg641Lys	missense_variant	Exon 8 of 10	ENST00000423345.5	NP_115528.4
PRAM1	XM_011528352.3	c.1928G>A	p.Arg643Lys	missense_variant	Exon 8 of 9		XP_011526654.1
PRAM1	XM_005272502.3	c.1922G>A	p.Arg641Lys	missense_variant	Exon 8 of 9		XP_005272559.1
PRAM1	XM_011528353.3	c.1928G>A	p.Arg643Lys	missense_variant	Exon 8 of 10		XP_011526655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRAM1	ENST00000423345.5	c.1922G>A	p.Arg641Lys	missense_variant	Exon 8 of 10	1	NM_032152.5	ENSP00000408342.2
PRAM1	ENST00000594696.1	n.1212G>A		non_coding_transcript_exon_variant	Exon 4 of 6	5
PRAM1	ENST00000599698.5	n.298G>A		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726250

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1922G>A (p.R641K) alteration is located in exon 8 (coding exon 8) of the PRAM1 gene. This alteration results from a G to A substitution at nucleotide position 1922, causing the arginine (R) at amino acid position 641 to be replaced by a lysine (K). 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	0.62
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.95	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.014	D
Sift4G	Benign	0.078	T
Vest4		0.66
MVP		0.62
MPC		0.58
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.26
gMVP		0.79

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

Other links and lift over

dbSNP: rs1295870494; hg19: chr19-8555378;