15-75640002-C-T

Variant names:

• chr15-75640002-C-T
• rs746369854
• NM_018285.4:c.167G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018285.4(IMP3):​c.167G>A​(p.Arg56His) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,449,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R56P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: IMP3 NM_018285.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.40

Genes affected

IMP3 (HGNC:14497): (IMP U3 small nucleolar ribonucleoprotein 3) This gene encodes the human homolog of the yeast Imp3 protein. The protein localizes to the nucleoli and interacts with the U3 snoRNP complex. The protein contains an S4 domain. [provided by RefSeq, Jul 2008]

ENSG00000275454 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMP3	NM_018285.4	c.167G>A	p.Arg56His	missense_variant	Exon 1 of 1	ENST00000403490.3	NP_060755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMP3	ENST00000403490.3	c.167G>A	p.Arg56His	missense_variant	Exon 1 of 1	6	NM_018285.4	ENSP00000385217.1
IMP3	ENST00000314852.2	c.167G>A	p.Arg56His	missense_variant	Exon 2 of 2	2		ENSP00000326981.2
ENSG00000275454	ENST00000621523.1	n.243C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1449312 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720160

African (AFR) AF: 0.00 AC: 0 AN: 33176

American (AMR) AF: 0.00 AC: 0 AN: 43186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39026

South Asian (SAS) AF: 0.00 AC: 0 AN: 85154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1106972

Other (OTH) AF: 0.00 AC: 0 AN: 59862

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		5.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.87	P;P
Vest4		0.61
MutPred		0.62		Loss of methylation at R56 (P = 0.0253);Loss of methylation at R56 (P = 0.0253);
MVP		0.71
MPC		0.77
ClinPred		0.99	D
GERP RS		6.1
PromoterAI		-0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.69
Mutation Taster		=51/49	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

Publications

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Other links and lift over

dbSNP: rs746369854; hg19: chr15-75932343;