rs201997946

Variant names:

• chr11-125893870-T-A
• rs201997946
• NM_031307.4:c.1361A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-125893870-T-A
• chr11-125893870-T-C
• chr11-125893870-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031307.4(PUS3):​c.1361A>T​(p.Asn454Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. N454S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUS3 NM_031307.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.269

Genes affected

PUS3 (HGNC:25461): (pseudouridine synthase 3) The protein encoded by this gene catalyzes the formation of tRNA pseudouridine from tRNA uridine at position 39 in the anticodon stem and loop of transfer RNAs. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

HYLS1 (HGNC:26558): (HYLS1 centriolar and ciliogenesis associated) This gene encodes a protein localized to the cytoplasm. Mutations in this gene are associated with hydrolethalus syndrome. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06635091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUS3	NM_031307.4	c.1361A>T	p.Asn454Ile	missense_variant	Exon 4 of 4	ENST00000227474.8	NP_112597.4
HYLS1	NM_001134793.2	c.-26+2398T>A		intron_variant	Intron 2 of 2	ENST00000425380.7	NP_001128265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUS3	ENST00000227474.8	c.1361A>T	p.Asn454Ile	missense_variant	Exon 4 of 4	1	NM_031307.4	ENSP00000227474.3
HYLS1	ENST00000425380.7	c.-26+2398T>A		intron_variant	Intron 2 of 2	3	NM_001134793.2	ENSP00000414884.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	10
DANN	Benign	0.96
DEOGEN2	Benign	0.0089	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.70	.;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;M;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.049
Sift	Benign	0.031	D;D;.
Sift4G	Benign	0.19	T;T;T
Polyphen		0.12	B;B;.
Vest4		0.23
MutPred		0.13		Loss of solvent accessibility (P = 0.0058);Loss of solvent accessibility (P = 0.0058);.;
MVP		0.47
MPC		0.12
ClinPred		0.057	T
GERP RS		-2.4
Varity_R		0.078
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs201997946; hg19: chr11-125763765;