8-98140867-C-T

Variant names:

• chr8-98140867-C-T
• rs769183311
• NM_001145860.2:c.1573C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001145860.2(POP1):​c.1573C>T​(p.Pro525Ser) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P525P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.35
• Publications: 1 publications found

Genes affected

POP1 (HGNC:30129): (POP1 homolog, ribonuclease P/MRP subunit) This gene encodes the protein subunit of two different small nucleolar ribonucleoprotein complexes: the endoribonuclease for mitochondrial RNA processing complex and the ribonuclease P complex. The encoded protein is a ribonuclease that localizes to the nucleus and functions in pre-RNA processing. This protein is also an autoantigen in patients suffering from connective tissue diseases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2009]

POP1 Gene-Disease associations (from GenCC):

• anauxetic dysplasia 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• anauxetic dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-98140867-C-T is Pathogenic according to our data. Variant chr8-98140867-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 393588.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08873084). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POP1	NM_001145860.2	c.1573C>T	p.Pro525Ser	missense_variant	Exon 11 of 16	ENST00000401707.7	NP_001139332.1
POP1	NM_001145861.2	c.1573C>T	p.Pro525Ser	missense_variant	Exon 11 of 16		NP_001139333.1
POP1	NM_015029.3	c.1573C>T	p.Pro525Ser	missense_variant	Exon 11 of 16		NP_055844.2
POP1	XM_011516801.3	c.1573C>T	p.Pro525Ser	missense_variant	Exon 11 of 12		XP_011515103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POP1	ENST00000401707.7	c.1573C>T	p.Pro525Ser	missense_variant	Exon 11 of 16	2	NM_001145860.2	ENSP00000385787.2
POP1	ENST00000349693.3	c.1573C>T	p.Pro525Ser	missense_variant	Exon 11 of 16	1		ENSP00000339529.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251356 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000616

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 Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000256 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Anauxetic dysplasia 2 Pathogenic:1

Apr 10, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.64	.;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
PhyloP100		1.4
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.13
Sift	Benign	0.15	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.012	B;B
Vest4		0.092
MVP		0.33
MPC		0.20
ClinPred		0.093	T
GERP RS		-0.58
Varity_R		0.17
gMVP		0.34
Mutation Taster		=34/66	disease causing (ClinVar)

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: rs769183311; hg19: chr8-99153095;