8-98140825-G-T

Variant names:

• chr8-98140825-G-T
• rs1060505025
• NM_001145860.2:c.1531G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001145860.2(POP1):​c.1531G>T​(p.Asp511Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 8-98140825-G-T is Pathogenic according to our data. Variant chr8-98140825-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 417738.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145860.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POP1	NM_001145860.2	MANE Select	c.1531G>T	p.Asp511Tyr	missense	Exon 11 of 16	NP_001139332.1
	POP1	NM_001145861.2		c.1531G>T	p.Asp511Tyr	missense	Exon 11 of 16	NP_001139333.1
	POP1	NM_015029.3		c.1531G>T	p.Asp511Tyr	missense	Exon 11 of 16	NP_055844.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POP1	ENST00000401707.7	TSL:2 MANE Select	c.1531G>T	p.Asp511Tyr	missense	Exon 11 of 16	ENSP00000385787.2
	POP1	ENST00000349693.3	TSL:1	c.1531G>T	p.Asp511Tyr	missense	Exon 11 of 16	ENSP00000339529.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.78		Loss of disorder (P = 0.0263)
MVP		0.94
MPC		0.82
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060505025; hg19: chr8-99153053; COSMIC: COSV62894176;