19-8498283-C-T

Variant names:

• chr19-8498283-C-T
• rs530402541
• NM_032152.5:c.1439G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032152.5(PRAM1):​c.1439G>A​(p.Arg480Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,752 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: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PRAM1 NM_032152.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.44
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052085906).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032152.5. 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
	PRAM1	NM_032152.5	MANE Select	c.1439G>A	p.Arg480Gln	missense	Exon 3 of 10	NP_115528.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRAM1	ENST00000423345.5	TSL:1 MANE Select	c.1439G>A	p.Arg480Gln	missense	Exon 3 of 10	ENSP00000408342.2	Q96QH2
	PRAM1	ENST00000880309.1		c.1439G>A	p.Arg480Gln	missense	Exon 3 of 10	ENSP00000550368.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243596 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459752 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726020

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111362

Other (OTH) AF: 0.0000166 AC: 1 AN: 60284

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

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	0.089
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.3
DANN	Benign	0.90
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.99	T
PhyloP100		-1.4
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.015
Sift	Benign	0.32	T
Sift4G	Benign	0.35	T
Vest4		0.081
MVP		0.099
MPC		0.16
ClinPred		0.13	T
GERP RS		-6.8
Varity_R		0.035
gMVP		0.091
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs530402541; hg19: chr19-8563167; COSMIC: COSV55314734; COSMIC: COSV55314734;