19-49449600-T-C

Variant summary

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

The NM_017916.3(PIH1D1):c.212A>G(p.His71Arg) 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 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIH1D1 NM_017916.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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=0.2473835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIH1D1	NM_017916.3	c.212A>G	p.His71Arg	missense_variant	3/9	ENST00000262265.10
PIH1D1	XM_047439024.1	c.212A>G	p.His71Arg	missense_variant	3/8
PIH1D1	XM_047439025.1	c.303A>G	p.Pro101=	synonymous_variant	3/6
PIH1D1	XM_024451570.2	c.-108A>G		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIH1D1	ENST00000262265.10	c.212A>G	p.His71Arg	missense_variant	3/9	1	NM_017916.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

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.: 32

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

Aug 14, 2023

The c.212A>G (p.H71R) alteration is located in exon 3 (coding exon 3) of the PIH1D1 gene. This alteration results from a A to G substitution at nucleotide position 212, causing the histidine (H) at amino acid position 71 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	Benign	0.29
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	21
Dann	Benign	0.67
DEOGEN2	Benign	0.0097	T;T;.;T;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;.;.;.;.
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N;.;.;.;.;.
REVEL	Benign	0.098
Sift	Benign	0.70	T;.;.;.;.;.
Sift4G	Benign	0.70	T;T;.;.;T;T
Polyphen		0.26	B;B;.;.;.;.
Vest4		0.39
MutPred		0.65		Gain of disorder (P = 0.0588);Gain of disorder (P = 0.0588);.;Gain of disorder (P = 0.0588);.;Gain of disorder (P = 0.0588);
MVP		0.25
MPC		0.95
ClinPred		0.66	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.66

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: chr19-49952857;