19-49450806-A-T

Variant summary

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

The NM_017916.3(PIH1D1):c.133T>A(p.Ser45Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PIH1D1 NM_017916.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

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]

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=0.16157722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIH1D1	NM_017916.3	c.133T>A	p.Ser45Thr	missense_variant	2/9	ENST00000262265.10
PIH1D1	XM_047439024.1	c.133T>A	p.Ser45Thr	missense_variant	2/8
PIH1D1	XM_047439025.1	c.224T>A	p.Ile75Asn	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIH1D1	ENST00000262265.10	c.133T>A	p.Ser45Thr	missense_variant	2/9	1	NM_017916.3	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461038 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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

Jan 30, 2024

The c.133T>A (p.S45T) alteration is located in exon 2 (coding exon 2) of the PIH1D1 gene. This alteration results from a T to A substitution at nucleotide position 133, causing the serine (S) at amino acid position 45 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.0068	T;T;.;T;.;T
Eigen	Benign	-0.032
Eigen_PC	Benign	0.0034
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.88	N;.;.;.;.;.
REVEL	Benign	0.092
Sift	Benign	0.24	T;.;.;.;.;.
Sift4G	Benign	0.40	T;T;.;.;T;T
Polyphen		0.099	B;B;.;.;.;.
Vest4		0.32
MutPred		0.45		Loss of glycosylation at S45 (P = 0.0493);Loss of glycosylation at S45 (P = 0.0493);.;Loss of glycosylation at S45 (P = 0.0493);.;Loss of glycosylation at S45 (P = 0.0493);
MVP		0.22
MPC		0.62
ClinPred		0.68	D
GERP RS		4.4
Varity_R		0.14
gMVP		0.55

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.

Other links and lift over

hg19: chr19-49954063;