10-15103825-G-A

Variant names:

• chr10-15103825-G-A
• rs145237477
• NM_183005.5:c.511G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_183005.5(RPP38):​c.511G>A​(p.Val171Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V171F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: RPP38 NM_183005.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53
• Publications: 3 publications found

Genes affected

RPP38 (HGNC:30329): (ribonuclease P/MRP subunit p38) Enables ribonuclease P RNA binding activity. Contributes to ribonuclease P activity. Involved in tRNA 5'-leader removal. Located in fibrillar center. Part of multimeric ribonuclease P complex. [provided by Alliance of Genome Resources, Apr 2022]

NMT2 (HGNC:7858): (N-myristoyltransferase 2) This gene encodes one of two N-myristoyltransferase proteins. N-terminal myristoylation is a lipid modification that is involved in regulating the function and localization of signaling proteins. The encoded protein catalyzes the addition of a myristoyl group to the N-terminal glycine residue of many signaling proteins, including the human immunodeficiency virus type 1 (HIV-1) proteins, Gag and Nef. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090504915).
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPP38	NM_183005.5	c.511G>A	p.Val171Ile	missense_variant	Exon 3 of 3	ENST00000378197.5	NP_892117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPP38	ENST00000378197.5	c.511G>A	p.Val171Ile	missense_variant	Exon 3 of 3	1	NM_183005.5	ENSP00000367439.4

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251220 AF XY: 0.000169

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000240 AC: 351 AN: 1461834 Hom.: 0 Cov.: 34 AF XY: 0.000245 AC XY: 178 AN XY: 727208

African (AFR) AF: 0.000119 AC: 4 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000306 AC: 340 AN: 1112010

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74424

African (AFR) AF: 0.000120 AC: 5 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68010

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.511G>A (p.V171I) alteration is located in exon 3 (coding exon 1) of the RPP38 gene. This alteration results from a G to A substitution at nucleotide position 511, causing the valine (V) at amino acid position 171 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0054	T;T;T;T
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.61	.;T;.;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.091	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.8	M;M;M;M
PhyloP100		3.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.23	N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.19	T;.;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.88	P;P;P;P
Vest4		0.078
MVP		0.30
MPC		0.38
ClinPred		0.094	T
GERP RS		4.8
Varity_R		0.18
gMVP		0.25
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs145237477; hg19: chr10-15145824; COSMIC: COSV100975456; COSMIC: COSV100975456;