19-49446596-C-A

Variant names:

• chr19-49446596-C-A
• rs2079024227
• NM_017916.3:c.786G>T

Variant summary

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

The NM_017916.3(PIH1D1):​c.786G>T​(p.Gln262His) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q262K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIH1D1 NM_017916.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0560
• Publications: 0 publications found

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]

ENSG00000305589 (HGNC:):

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=0.12617618).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017916.3. 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
	PIH1D1	NM_017916.3	MANE Select	c.786G>T	p.Gln262His	missense	Exon 8 of 9	NP_060386.1	Q9NWS0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIH1D1	ENST00000262265.10	TSL:1 MANE Select	c.786G>T	p.Gln262His	missense	Exon 8 of 9	ENSP00000262265.4	Q9NWS0-1
	PIH1D1	ENST00000943281.1		c.891G>T	p.Gln297His	missense	Exon 8 of 9	ENSP00000613340.1
	PIH1D1	ENST00000911068.1		c.837G>T	p.Gln279His	missense	Exon 9 of 10	ENSP00000581127.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.056
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.040
Sift	Benign	0.16	T
Sift4G	Benign	0.14	T
Polyphen		0.26	B
Vest4		0.21
MutPred		0.47		Gain of disorder (P = 0.1297)
MVP		0.12
MPC		0.55
ClinPred		0.12	T
GERP RS		-1.2
Varity_R		0.24
gMVP		0.29
Mutation Taster		=89/11	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

dbSNP: rs2079024227; hg19: chr19-49949853;