chr1-1308943-C-T

Variant names:

• chr1-1308943-C-T
• rs200089551
• NM_153339.3:c.106C>T

Variant summary

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

The NM_153339.3(PUSL1):​c.106C>T​(p.Arg36Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000237 in 1,268,044 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. R36S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: PUSL1 NM_153339.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.214
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.106C>T	p.Arg36Cys	missense	Exon 2 of 8	NP_699170.1	Q8N0Z8-1
	PUSL1	NM_001346116.2		c.106C>T	p.Arg36Cys	missense	Exon 2 of 8	NP_001333045.1
	PUSL1	NR_144369.2		n.125-143C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUSL1	ENST00000379031.10	TSL:1 MANE Select	c.106C>T	p.Arg36Cys	missense	Exon 2 of 8	ENSP00000368318.5	Q8N0Z8-1
	PUSL1	ENST00000892133.1		c.106C>T	p.Arg36Cys	missense	Exon 2 of 8	ENSP00000562192.1
	PUSL1	ENST00000892132.1		c.85C>T	p.Arg29Cys	missense	Exon 2 of 8	ENSP00000562191.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000354 AC: 2 AN: 56430 AF XY: 0.0000317

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00000237 AC: 3 AN: 1268044 Hom.: 0 Cov.: 33 AF XY: 0.00000486 AC XY: 3 AN XY: 616698

African (AFR) AF: 0.00 AC: 0 AN: 25134

American (AMR) AF: 0.00 AC: 0 AN: 16656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17816

East Asian (EAS) AF: 0.00 AC: 0 AN: 29828

South Asian (SAS) AF: 0.00 AC: 0 AN: 58852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3586

European-Non Finnish (NFE) AF: 0.00000293 AC: 3 AN: 1022628

Other (OTH) AF: 0.00 AC: 0 AN: 51762

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000909 AC: 1

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	Benign	0.23
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Benign	0.020
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.21
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.23
Sift	Benign	0.057	T
Sift4G	Uncertain	0.054	T
Polyphen		0.99	D
Vest4		0.51
MutPred		0.48		Loss of MoRF binding (P = 0.0083)
MVP		0.46
MPC		0.43
ClinPred		0.35	T
GERP RS		4.5
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.22
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200089551; hg19: chr1-1244323;