11-112070638-A-G

Position:

• chr11-112070638-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138789.4(PIH1D2):​c.611T>C​(p.Leu204Ser) 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. 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)
• Consequence: PIH1D2 NM_138789.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35452694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIH1D2	NM_138789.4	c.611T>C	p.Leu204Ser	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.611T>C	p.Leu204Ser	missense_variant	5/6	5	NM_138789.4	ENSP00000280350	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Oct 04, 2022

The c.611T>C (p.L204S) alteration is located in exon 5 (coding exon 4) of the PIH1D2 gene. This alteration results from a T to C substitution at nucleotide position 611, causing the leucine (L) at amino acid position 204 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.62
DEOGEN2	Benign	0.0020	.;.;T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.66	.;T;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.8	M;M;M;M;M
MutationTaster	Benign	0.74	N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.99	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.31	T;T;T;T;T
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		0.078	.;.;B;B;.
Vest4		0.36
MutPred		0.74		Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);
MVP		0.47
MPC		0.22
ClinPred		0.25	T
GERP RS		4.7
Varity_R		0.085
gMVP		0.53

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: chr11-111941362;