19-8498418-C-A

Variant names:

• chr19-8498418-C-A
• rs766521799
• NM_032152.5:c.1390G>T

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.1390G>T​(p.Val464Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,424,948 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. 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. V464M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRAM1 NM_032152.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.507
• 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: 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=0.023722023).

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.1390G>T	p.Val464Leu	missense	Exon 2 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.1390G>T	p.Val464Leu	missense	Exon 2 of 10	ENSP00000408342.2	Q96QH2
	PRAM1	ENST00000880309.1		c.1390G>T	p.Val464Leu	missense	Exon 2 of 10	ENSP00000550368.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1424948 Hom.: 0 Cov.: 32 AF XY: 0.00000284 AC XY: 2 AN XY: 704686

African (AFR) AF: 0.00 AC: 0 AN: 32702

American (AMR) AF: 0.00 AC: 0 AN: 40782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24176

East Asian (EAS) AF: 0.00 AC: 0 AN: 38762

South Asian (SAS) AF: 0.00 AC: 0 AN: 81704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1091928

Other (OTH) AF: 0.00 AC: 0 AN: 58666

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.028
DANN	Benign	0.47
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.51
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.015
Sift	Benign	0.99	T
Sift4G	Benign	0.41	T
Vest4		0.025
MVP		0.055
MPC		0.12
ClinPred		0.13	T
GERP RS		-7.1
Varity_R		0.050
gMVP		0.090
Mutation Taster		=99/1	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: rs766521799; hg19: chr19-8563302;