Variant 1-23786370-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020362.5(PITHD1):c.481G>A(p.Gly161Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,454,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PITHD1
NM_020362.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.92

Variant links:

Genes affected

PITHD1 (HGNC:25022): (PITH domain containing 1) Involved in positive regulation of megakaryocyte differentiation and positive regulation of transcription, DNA-templated. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PITHD1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITHD1	NM_020362.5 linkuse as main transcript	c.481G>A	p.Gly161Arg	missense_variant	5/6	ENST00000246151.9	NP_065095.2
PITHD1	XM_011541804.2 linkuse as main transcript	c.202G>A	p.Gly68Arg	missense_variant	4/5		XP_011540106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITHD1	ENST00000246151.9 linkuse as main transcript	c.481G>A	p.Gly161Arg	missense_variant	5/6	1	NM_020362.5	ENSP00000246151	P1	Q9GZP4-1
PITHD1	ENST00000374524.1 linkuse as main transcript	c.142G>A	p.Gly48Arg	missense_variant	3/4	3		ENSP00000363648
PITHD1	ENST00000415372.1 linkuse as main transcript	c.202G>A	p.Gly68Arg	missense_variant	3/3	2		ENSP00000405957

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1454946

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

723892

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:

0.00000542

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

Dec 14, 2023

The c.481G>A (p.G161R) alteration is located in exon 5 (coding exon 5) of the PITHD1 gene. This alteration results from a G to A substitution at nucleotide position 481, causing the glycine (G) at amino acid position 161 to be replaced by an arginine (R). 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

0.82

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.3

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.1

D;D;D

REVEL

Pathogenic

0.90

Sift

Benign

0.052

T;D;T

Sift4G

Uncertain

0.019

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.87

MutPred

0.80

Gain of MoRF binding (P = 0.0217);.;.;

MVP

0.66

MPC

1.2

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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