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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100818.2. 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
	PID1	NM_001100818.2	MANE Select	c.178G>A	p.Val60Ile	missense splice_region	Exon 3 of 3	NP_001094288.1	Q7Z2X4-4
	PID1	NM_001330156.1		c.277G>A	p.Val93Ile	missense splice_region	Exon 3 of 3	NP_001317085.1	Q7Z2X4-1
	PID1	NM_017933.5		c.271G>A	p.Val91Ile	missense splice_region	Exon 4 of 4	NP_060403.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PID1	ENST00000392055.8	TSL:2 MANE Select	c.178G>A	p.Val60Ile	missense splice_region	Exon 3 of 3	ENSP00000375908.3	Q7Z2X4-4
	PID1	ENST00000409462.1	TSL:1	c.31G>A	p.Val11Ile	missense splice_region	Exon 2 of 2	ENSP00000386826.1	Q7Z2X4-3
	PID1	ENST00000354069.6	TSL:3	c.277G>A	p.Val93Ile	missense splice_region	Exon 3 of 3	ENSP00000283937.8	Q7Z2X4-1

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

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	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
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	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;