15-41517666-T-C

Variant names:

• chr15-41517666-T-C
• rs1271704600
• NM_015540.4:c.4058A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015540.4(RPAP1):​c.4058A>G​(p.Tyr1353Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RPAP1 NM_015540.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

Genes affected

RPAP1 (HGNC:24567): (RNA polymerase II associated protein 1) This protein forms part of the RNA polymerase II (RNAPII) enzyme complex and may recruit RNAPII to chromatin through its interaction with acetylated histones. [provided by RefSeq, Jul 2012]

ACMG classification

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=0.22665522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPAP1	NM_015540.4	c.4058A>G	p.Tyr1353Cys	missense_variant	Exon 25 of 25	ENST00000304330.9	NP_056355.2
RPAP1	XM_005254297.2	c.4058A>G	p.Tyr1353Cys	missense_variant	Exon 25 of 25		XP_005254354.1
RPAP1	XM_047432374.1	c.3878A>G	p.Tyr1293Cys	missense_variant	Exon 24 of 24		XP_047288330.1
RPAP1	XM_047432375.1	c.3878A>G	p.Tyr1293Cys	missense_variant	Exon 24 of 24		XP_047288331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPAP1	ENST00000304330.9	c.4058A>G	p.Tyr1353Cys	missense_variant	Exon 25 of 25	1	NM_015540.4	ENSP00000306123.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250584 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460590 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726446

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4058A>G (p.Y1353C) alteration is located in exon 25 (coding exon 24) of the RPAP1 gene. This alteration results from a A to G substitution at nucleotide position 4058, causing the tyrosine (Y) at amino acid position 1353 to be replaced by a cysteine (C). 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	0.32
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Benign	0.0083	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.23	T
PROVEAN	Benign	-0.22	N
Sift	Pathogenic	0.0	D
Vest4		0.19
MVP		0.42
ClinPred		0.99	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1271704600; hg19: chr15-41809864;