15-41466162-C-T

Variant names:

• chr15-41466162-C-T
• NM_015138.5:c.799C>T

Variant summary

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

The NM_015138.5(RTF1):​c.799C>T​(p.Arg267Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,270 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R267Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RTF1 NM_015138.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 0 publications found

Genes affected

RTF1 (HGNC:28996): (RTF1 homolog, Paf1/RNA polymerase II complex component) This locus may represent a gene involved in regulation of transcription elongation and chromatin remodeling, based on studies of similar proteins in other organisms. The encoded protein may bind single-stranded DNA. [provided by RefSeq, Sep 2010]

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_015138.5. 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
	RTF1	NM_015138.5	MANE Select	c.799C>T	p.Arg267Trp	missense	Exon 6 of 18	NP_055953.3	Q92541

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTF1	ENST00000389629.9	TSL:1 MANE Select	c.799C>T	p.Arg267Trp	missense	Exon 6 of 18	ENSP00000374280.4	Q92541
	RTF1	ENST00000925186.1		c.799C>T	p.Arg267Trp	missense	Exon 6 of 17	ENSP00000595245.1
	RTF1	ENST00000925187.1		c.688C>T	p.Arg230Trp	missense	Exon 5 of 17	ENSP00000595246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1433270 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 710704

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32836

American (AMR) AF: 0.00 AC: 0 AN: 38928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25364

East Asian (EAS) AF: 0.00 AC: 0 AN: 39080

South Asian (SAS) AF: 0.00 AC: 0 AN: 81106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1099080

Other (OTH) AF: 0.00 AC: 0 AN: 59282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.0070
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.076	B
Vest4		0.74
MutPred		0.25		Gain of ubiquitination at K265 (P = 0.0444)
MVP		0.53
MPC		1.2
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.18
Mutation Taster		=37/63	disease causing

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

hg19: chr15-41758360;