rs1060505025

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-98140825-G-A
• chr8-98140825-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001145860.2(POP1):​c.1531G>A​(p.Asp511Asn) 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. 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. D511Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POP1	NM_001145860.2	c.1531G>A	p.Asp511Asn	missense_variant	Exon 11 of 16	ENST00000401707.7	NP_001139332.1
POP1	NM_001145861.2	c.1531G>A	p.Asp511Asn	missense_variant	Exon 11 of 16		NP_001139333.1
POP1	NM_015029.3	c.1531G>A	p.Asp511Asn	missense_variant	Exon 11 of 16		NP_055844.2
POP1	XM_011516801.3	c.1531G>A	p.Asp511Asn	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.1531G>A	p.Asp511Asn	missense_variant	Exon 11 of 16	2	NM_001145860.2	ENSP00000385787.2
POP1	ENST00000349693.3	c.1531G>A	p.Asp511Asn	missense_variant	Exon 11 of 16	1		ENSP00000339529.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.9	M;M
PhyloP100		9.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.75		Gain of glycosylation at T508 (P = 0.0704);Gain of glycosylation at T508 (P = 0.0704);
MVP		0.90
MPC		0.72
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.82
gMVP		0.85
Mutation Taster		=19/81	disease causing

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: rs1060505025; hg19: chr8-99153053;