5-65563375-C-T

Variant names:

• chr5-65563375-C-T
• rs762283295
• NM_015342.4:c.65C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001278926.2(PPWD1):​c.-63C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PPWD1 NM_001278926.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

Genes affected

PPWD1 (HGNC:28954): (peptidylprolyl isomerase domain and WD repeat containing 1) Enables cyclosporin A binding activity and peptidyl-prolyl cis-trans isomerase activity. Involved in protein peptidyl-prolyl isomerization. Located in nuclear body. Part of catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

CENPK (HGNC:29479): (centromere protein K) CENPK is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006 [PubMed 16622420]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05883196).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278926.2. 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
	PPWD1	NM_015342.4	MANE Select	c.65C>T	p.Pro22Leu	missense	Exon 1 of 11	NP_056157.1	Q96BP3-1
	PPWD1	NM_001278926.2		c.-63C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001265855.1	F5H7P7
	PPWD1	NM_001278927.2		c.-183C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001265856.1	B4DP34

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPWD1	ENST00000261308.10	TSL:1 MANE Select	c.65C>T	p.Pro22Leu	missense	Exon 1 of 11	ENSP00000261308.4	Q96BP3-1
	PPWD1	ENST00000535264.5	TSL:2	c.-63C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000442371.1	F5H7P7
	PPWD1	ENST00000538977.5	TSL:2	c.-301C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000444496.1	Q96BP3-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251444 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 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	0.079
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.096
Sift	Benign	0.095	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.24		Loss of sheet (P = 0.0054)
MVP		0.57
MPC		0.29
ClinPred		0.088	T
GERP RS		3.1
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.34
Mutation Taster		=95/5	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: rs762283295; hg19: chr5-64859202;