1-1308657-C-T

Variant names:

• chr1-1308657-C-T
• rs1485192589
• NM_153339.3:c.14C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153339.3(PUSL1):​c.14C>T​(p.Pro5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,381,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P5Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PUSL1 NM_153339.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 0 publications found

Genes affected

PUSL1 (HGNC:26914): (pseudouridine synthase like 1) Predicted to enable pseudouridine synthase activity. Predicted to be involved in tRNA pseudouridine synthesis. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACAP3 (HGNC:16754): (ArfGAP with coiled-coil, ankyrin repeat and PH domains 3) Predicted to enable GTPase activator activity and metal ion binding activity. Predicted to be involved in regulation of catalytic activity. Predicted to act upstream of or within neuron migration and regulation of neuron projection development. Predicted to be located in growth cone. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06940225).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153339.3. 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
	PUSL1	NM_153339.3	MANE Select	c.14C>T	p.Pro5Leu	missense	Exon 1 of 8	NP_699170.1	Q8N0Z8-1
	PUSL1	NM_001346116.2		c.14C>T	p.Pro5Leu	missense	Exon 1 of 8	NP_001333045.1
	PUSL1	NR_144369.2		n.61C>T		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUSL1	ENST00000379031.10	TSL:1 MANE Select	c.14C>T	p.Pro5Leu	missense	Exon 1 of 8	ENSP00000368318.5	Q8N0Z8-1
	PUSL1	ENST00000892133.1		c.14C>T	p.Pro5Leu	missense	Exon 1 of 8	ENSP00000562192.1
	PUSL1	ENST00000892132.1		c.14C>T	p.Pro5Leu	missense	Exon 1 of 8	ENSP00000562191.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1381918 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 684666

African (AFR) AF: 0.00 AC: 0 AN: 28564

American (AMR) AF: 0.00 AC: 0 AN: 33880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24128

East Asian (EAS) AF: 0.00 AC: 0 AN: 31084

South Asian (SAS) AF: 0.00 AC: 0 AN: 77892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48820

Middle Eastern (MID) AF: 0.000226 AC: 1 AN: 4426

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076352

Other (OTH) AF: 0.00 AC: 0 AN: 56772

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.8
DANN	Benign	0.81
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-1.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.29		Gain of MoRF binding (P = 0.0166)
MVP		0.12
MPC		0.080
ClinPred		0.035	T
GERP RS		-0.23
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.023
gMVP		0.25
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs1485192589; hg19: chr1-1244037;