chr6-4996308-G-T

Variant names:

• chr6-4996308-G-T
• rs1759380758
• NM_006638.4:c.672C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006638.4(RPP40):​c.672C>A​(p.Ser224Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: RPP40 NM_006638.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.582
• Publications: 0 publications found

Genes affected

RPP40 (HGNC:20992): (ribonuclease P/MRP subunit p40) Enables ribonuclease P RNA binding activity. Contributes to ribonuclease P activity. Involved in tRNA 5'-leader removal. Part of multimeric ribonuclease P complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006638.4. 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
	RPP40	NM_006638.4	MANE Select	c.672C>A	p.Ser224Arg	missense	Exon 6 of 8	NP_006629.2	O75818-1
	RPP40	NM_001286132.2		c.603C>A	p.Ser201Arg	missense	Exon 5 of 7	NP_001273061.1	O75818-2
	RPP40	NM_001286133.2		c.546C>A	p.Ser182Arg	missense	Exon 5 of 7	NP_001273062.1	A0A087X1N3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPP40	ENST00000380051.7	TSL:5 MANE Select	c.672C>A	p.Ser224Arg	missense	Exon 6 of 8	ENSP00000369391.2	O75818-1
	RPP40	ENST00000319533.9	TSL:1	c.603C>A	p.Ser201Arg	missense	Exon 5 of 7	ENSP00000317998.5	O75818-2
	RPP40	ENST00000618533.4	TSL:5	c.546C>A	p.Ser182Arg	missense	Exon 5 of 7	ENSP00000484334.1	A0A087X1N3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.58
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.016	D
Sift4G	Benign	0.071	T
Polyphen		0.97	D
Vest4		0.64
MutPred		0.49		Loss of disorder (P = 0.0764)
MVP		0.51
MPC		0.79
ClinPred		0.93	D
GERP RS		2.0
Varity_R		0.45
gMVP		0.57
Mutation Taster		=70/30	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: rs1759380758; hg19: chr6-4996542;