11-112070656-T-C

Variant names:

• chr11-112070656-T-C
• NM_138789.4:c.593A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138789.4(PIH1D2):​c.593A>G​(p.Asp198Gly) 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 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: PIH1D2 NM_138789.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.598
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14275572).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138789.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIH1D2	NM_138789.4	MANE Select	c.593A>G	p.Asp198Gly	missense	Exon 5 of 6	NP_620144.1	Q8WWB5-1
	PIH1D2	NM_001439211.1		c.593A>G	p.Asp198Gly	missense	Exon 5 of 6	NP_001426140.1
	PIH1D2	NM_001082619.2		c.593A>G	p.Asp198Gly	missense	Exon 5 of 6	NP_001076088.1	Q8WWB5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIH1D2	ENST00000280350.10	TSL:5 MANE Select	c.593A>G	p.Asp198Gly	missense	Exon 5 of 6	ENSP00000280350.4	Q8WWB5-1
	PIH1D2	ENST00000532211.5	TSL:5	c.593A>G	p.Asp198Gly	missense	Exon 5 of 6	ENSP00000431841.1	Q8WWB5-1
	PIH1D2	ENST00000957365.1		c.593A>G	p.Asp198Gly	missense	Exon 4 of 5	ENSP00000627424.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111968

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.60
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.088
Sift	Benign	0.094	T
Sift4G	Benign	0.15	T
Polyphen		0.32	B
Vest4		0.096
MutPred		0.35		Loss of stability (P = 0.0613)
MVP		0.46
MPC		0.16
ClinPred		0.22	T
GERP RS		4.7
Varity_R		0.14
gMVP		0.38
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chr11-111941380;