Genetic Variant RPRML:p.Ala115Val (chr17-46978664-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_203400.5(RPRML):c.344C>T(p.Ala115Val) 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 benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RPRML
NM_203400.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56

Variant links:

Genes affected

RPRML (HGNC:32422): (reprimo like) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

RPRML links:

ENSG00000262633 (HGNC:):

ENSG00000262633 links:

LRRC37A2 (HGNC:32404): (leucine rich repeat containing 37 member A2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC37A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.079937845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPRML	NM_203400.5 link	c.344C>T	p.Ala115Val	missense_variant	Exon 1 of 1	ENST00000322329.5	NP_981945.1	Q8N4K4
LRRC37A2	XM_024450773.2 link	c.4810-70392G>A		intron_variant	Intron 10 of 10		XP_024306541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPRML	ENST00000322329.5 link	c.344C>T	p.Ala115Val	missense_variant	Exon 1 of 1	6	NM_203400.5	ENSP00000318032.3	Q8N4K4
ENSG00000262633	ENST00000571841.1 link	n.676+12038G>A		intron_variant	Intron 7 of 9	5		ENSP00000461460.1	E7EQ34
ENSG00000291209	ENST00000570478.5 link	n.184G>A		non_coding_transcript_exon_variant	Exon 1 of 4	4
ENSG00000262633	ENST00000639822.1 link	n.568+12038G>A		intron_variant	Intron 6 of 7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455602

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723756

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.344C>T (p.A115V) alteration is located in exon 1 (coding exon 1) of the RPRML gene. This alteration results from a C to T substitution at nucleotide position 344, causing the alanine (A) at amino acid position 115 to be replaced by a valine (V). 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

Benign

0.15

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0011

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.75

M_CAP

Benign

0.017

MetaRNN

Benign

0.080

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.17

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.56

REVEL

Benign

0.075

Sift

Benign

1.0

Sift4G

Benign

0.50

Polyphen

0.041

Vest4

0.21

MutPred

0.35

Loss of disorder (P = 0.0519);

MVP

0.030

MPC

1.1

ClinPred

0.79

GERP RS

3.9

Varity_R

0.17

gMVP

0.82

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over