1-23778567-C-T

Position:

• chr1-23778567-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020362.5(PITHD1):​c.52C>T​(p.Arg18Trp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PITHD1 NM_020362.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18936774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITHD1	NM_020362.5	c.52C>T	p.Arg18Trp	missense_variant	1/6	ENST00000246151.9	NP_065095.2
PITHD1	XM_011541804.2	c.-184C>T		5_prime_UTR_premature_start_codon_gain_variant	1/5		XP_011540106.1
PITHD1	XM_011541804.2	c.-184C>T		5_prime_UTR_variant	1/5		XP_011540106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITHD1	ENST00000246151.9	c.52C>T	p.Arg18Trp	missense_variant	1/6	1	NM_020362.5	ENSP00000246151.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1191188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 576964

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2024

The c.52C>T (p.R18W) alteration is located in exon 1 (coding exon 1) of the PITHD1 gene. This alteration results from a C to T substitution at nucleotide position 52, causing the arginine (R) at amino acid position 18 to be replaced by a tryptophan (W). 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	0.21
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.0036
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Benign	0.048	D
Sift4G	Uncertain	0.019	D
Polyphen		0.96	D
Vest4		0.22
MutPred		0.35		Loss of disorder (P = 0.0029);
MVP		0.67
MPC		2.3
ClinPred		0.85	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-24105057;