chr2-229026108-C-T

Variant names:

• chr2-229026108-C-T
• rs746316153
• NM_001100818.2:c.178G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001100818.2(PID1):​c.178G>A​(p.Val60Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,608,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: PID1 NM_001100818.2 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22
• Publications: 0 publications found

Genes affected

PID1 (HGNC:26084): (phosphotyrosine interaction domain containing 1) Involved in several processes, including mitochondrion morphogenesis; negative regulation of phosphate metabolic process; and positive regulation of macromolecule metabolic process. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PID1	NM_001100818.2	c.178G>A	p.Val60Ile	missense_variant, splice_region_variant	Exon 3 of 3	ENST00000392055.8	NP_001094288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PID1	ENST00000392055.8	c.178G>A	p.Val60Ile	missense_variant, splice_region_variant	Exon 3 of 3	2	NM_001100818.2	ENSP00000375908.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000324 AC: 8 AN: 246570 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1456584 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 724498

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.000202 AC: 9 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107666

Other (OTH) AF: 0.0000166 AC: 1 AN: 60168

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.000262 AC: 4 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.271G>A (p.V91I) alteration is located in exon 4 (coding exon 3) of the PID1 gene. This alteration results from a G to A substitution at nucleotide position 271, causing the valine (V) at amino acid position 91 to be replaced by an isoleucine (I). 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;T;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.4	.;.;.;M
PhyloP100		7.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.72	N;N;N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.55
MutPred		0.34		.;.;.;Loss of catalytic residue at V93 (P = 0.1254);
MVP		0.31
MPC		0.42
ClinPred		0.65	D
GERP RS		5.1
Varity_R		0.43
gMVP		0.52
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
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: rs746316153; hg19: chr2-229890824;