Variant 19-49447396-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017916.3(PIH1D1):c.553C>T(p.Pro185Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PIH1D1
NM_017916.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.08

Variant links:

Genes affected

PIH1D1 (HGNC:26075): (PIH1 domain containing 1) Enables several functions, including RNA polymerase I core promoter sequence-specific DNA binding activity; enzyme binding activity; and phosphoprotein binding activity. Involved in several processes, including box C/D snoRNP assembly; positive regulation of signal transduction; and regulation of cellular protein metabolic process. Located in cytoplasm and nucleolus. Part of R2TP complex and pre-snoRNP complex. [provided by Alliance of Genome Resources, Apr 2022]

PIH1D1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIH1D1	NM_017916.3 linkuse as main transcript	c.553C>T	p.Pro185Ser	missense_variant	6/9	ENST00000262265.10
PIH1D1	XM_047439024.1 linkuse as main transcript	c.553C>T	p.Pro185Ser	missense_variant	6/8
PIH1D1	XM_024451570.2 linkuse as main transcript	c.172C>T	p.Pro58Ser	missense_variant	3/6
PIH1D1	XM_047439025.1 linkuse as main transcript			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIH1D1	ENST00000262265.10 linkuse as main transcript	c.553C>T	p.Pro185Ser	missense_variant	6/9	1	NM_017916.3	P1	Q9NWS0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250828

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000205

AC:

AN:

1461346

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.553C>T (p.P185S) alteration is located in exon 6 (coding exon 6) of the PIH1D1 gene. This alteration results from a C to T substitution at nucleotide position 553, causing the proline (P) at amino acid position 185 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.41

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.035

T;T;.;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.69

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.0

D;.;.;.

REVEL

Uncertain

0.31

Sift

Uncertain

0.0080

D;.;.;.

Sift4G

Uncertain

0.027

D;D;.;.

Polyphen

1.0

D;D;.;.

Vest4

0.45

MutPred

0.70

Gain of phosphorylation at P185 (P = 0.0202);Gain of phosphorylation at P185 (P = 0.0202);.;.;

MVP

0.55

MPC

1.2

ClinPred

0.95

GERP RS

4.8

Varity_R

0.29

gMVP

0.48

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over