11-112070537-T-G

Position:

• chr11-112070537-T-G

Variant summary

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

The NM_138789.4(PIH1D2):​c.712A>C​(p.Lys238Gln) 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. 13/21 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)
• Consequence: PIH1D2 NM_138789.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

Genes affected

PIH1D2 (HGNC:25210): (PIH1 domain containing 2) Enables small GTPase binding activity. Predicted to be involved in box C/D snoRNP assembly and rRNA processing. Predicted to be part of R2TP complex and ribonucleoprotein complex. Predicted to be active 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=0.23236904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIH1D2	NM_138789.4	c.712A>C	p.Lys238Gln	missense_variant	5/6	ENST00000280350.10	NP_620144.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIH1D2	ENST00000280350.10	c.712A>C	p.Lys238Gln	missense_variant	5/6	5	NM_138789.4	ENSP00000280350	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 13, 2021

The c.712A>C (p.K238Q) alteration is located in exon 5 (coding exon 4) of the PIH1D2 gene. This alteration results from a A to C substitution at nucleotide position 712, causing the lysine (K) at amino acid position 238 to be replaced by a glutamine (Q). 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	0.093
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.0026	.;.;T;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	.;T;.;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M
MutationTaster	Benign	0.89	N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.54	N;N;N;N;N
REVEL	Benign	0.085
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.021	.;.;B;B;.
Vest4		0.21
MutPred		0.52		Loss of methylation at K238 (P = 0.0126);Loss of methylation at K238 (P = 0.0126);Loss of methylation at K238 (P = 0.0126);Loss of methylation at K238 (P = 0.0126);Loss of methylation at K238 (P = 0.0126);
MVP		0.54
MPC		0.13
ClinPred		0.25	T
GERP RS		6.2
Varity_R		0.15
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1865075615; hg19: chr11-111941261;