19-8490494-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032152.5(PRAM1):​c.1922G>C​(p.Arg641Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R641K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRAM1 NM_032152.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

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.1922G>C	p.Arg641Thr	missense	Exon 8 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.1922G>C	p.Arg641Thr	missense	Exon 8 of 10	ENSP00000408342.2	Q96QH2
	PRAM1	ENST00000880309.1		c.1934G>C	p.Arg645Thr	missense	Exon 8 of 10	ENSP00000550368.1
	PRAM1	ENST00000594696.1	TSL:5	n.1212G>C		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Benign	0.97
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.0	T
PhyloP100		2.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.19
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.015	D
Vest4		0.72
MVP		0.66
MPC		0.71
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.29
gMVP		0.80
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs1295870494; hg19: chr19-8555378;