17-5428245-A-T

Variant names:

• chr17-5428245-A-T
• rs202148178
• NM_001033002.4:c.630+34A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001160243.2(RPAIN):​c.664A>T​(p.Arg222Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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. R222G) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RPAIN NM_001160243.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.620
• Publications: 0 publications found

Genes affected

RPAIN (HGNC:28641): (RPA interacting protein) Predicted to enable metal ion binding activity. Acts upstream of or within several processes, including DNA metabolic process; protein import into nucleus; and response to UV. Located in PML body; cytoplasm; and fibrillar center. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000263272 (HGNC:):

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=0.061196297).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160243.2. 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
	RPAIN	NM_001033002.4	MANE Select	c.630+34A>T		intron	N/A	NP_001028174.2	Q86UA6-1
	RPAIN	NM_001160243.2		c.664A>T	p.Arg222Trp	missense	Exon 6 of 6	NP_001153715.1	Q86UA6-8
	RPAIN	NM_001160244.2		c.489+1946A>T		intron	N/A	NP_001153716.1	Q86UA6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPAIN	ENST00000381209.8	TSL:1 MANE Select	c.630+34A>T		intron	N/A	ENSP00000370606.3	Q86UA6-1
	RPAIN	ENST00000381208.9	TSL:1	c.489+1946A>T		intron	N/A	ENSP00000370605.5	Q86UA6-2
	RPAIN	ENST00000536255.6	TSL:1	c.314-4297A>T		intron	N/A	ENSP00000439939.2	Q86UA6-6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.8
DANN	Benign	0.67
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.62
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.026
Sift	Pathogenic	0.0	D
Vest4		0.31
MutPred		0.42		Loss of methylation at K221 (P = 0.0669)
MVP		0.27
MPC		0.11
ClinPred		0.036	T
GERP RS		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs202148178; hg19: chr17-5331565;