Variant 19-49447875-T-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.433A>T(p.Ile145Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 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: 6.8e-7 ( 0 hom. )

Consequence

PIH1D1
NM_017916.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.79

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.433A>T	p.Ile145Phe	missense_variant	5/9	ENST00000262265.10
PIH1D1	XM_047439024.1 linkuse as main transcript	c.433A>T	p.Ile145Phe	missense_variant	5/8
PIH1D1	XM_047439025.1 linkuse as main transcript	c.524A>T	p.His175Leu	missense_variant	5/6
PIH1D1	XM_024451570.2 linkuse as main transcript	c.52A>T	p.Ile18Phe	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIH1D1	ENST00000262265.10 linkuse as main transcript	c.433A>T	p.Ile145Phe	missense_variant	5/9	1	NM_017916.3	P1	Q9NWS0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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.:

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

Apr 07, 2023

The c.433A>T (p.I145F) alteration is located in exon 5 (coding exon 5) of the PIH1D1 gene. This alteration results from a A to T substitution at nucleotide position 433, causing the isoleucine (I) at amino acid position 145 to be replaced by a phenylalanine (F). 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

Pathogenic

0.73

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.054

T;T;.;T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.78

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.42

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;M;.;.;.

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.4

D;.;.;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.0060

D;.;.;.;.

Sift4G

Uncertain

0.011

D;D;.;.;D

Polyphen

0.99

D;D;.;.;.

Vest4

0.55

MutPred

0.67

Loss of catalytic residue at L141 (P = 0.3648);Loss of catalytic residue at L141 (P = 0.3648);.;.;.;

MVP

0.40

MPC

1.6

ClinPred

0.97

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.53

gMVP

0.71

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over