8-98127649-T-C

Variant names:

• chr8-98127649-T-C
• NM_001145860.2:c.197T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145860.2(POP1):​c.197T>C​(p.Leu66Pro) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: POP1 NM_001145860.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0450
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07841417).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POP1	NM_001145860.2	MANE Select	c.197T>C	p.Leu66Pro	missense	Exon 3 of 16	NP_001139332.1	Q99575
	POP1	NM_001145861.2		c.197T>C	p.Leu66Pro	missense	Exon 3 of 16	NP_001139333.1	Q99575
	POP1	NM_015029.3		c.197T>C	p.Leu66Pro	missense	Exon 3 of 16	NP_055844.2	Q99575

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POP1	ENST00000401707.7	TSL:2 MANE Select	c.197T>C	p.Leu66Pro	missense	Exon 3 of 16	ENSP00000385787.2	Q99575
	POP1	ENST00000349693.3	TSL:1	c.197T>C	p.Leu66Pro	missense	Exon 3 of 16	ENSP00000339529.3	Q99575
	POP1	ENST00000916453.1		c.197T>C	p.Leu66Pro	missense	Exon 3 of 16	ENSP00000586512.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.8
DANN	Benign	0.68
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.75	N
PhyloP100		0.045
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.0090
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.066
MutPred		0.20		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.25
MPC		0.30
ClinPred		0.026	T
GERP RS		0.83
Varity_R		0.053
gMVP		0.18
Mutation Taster		=90/10	polymorphism

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

hg19: chr8-99139877;