chr10-70533003-G-A

Position:

• chr10-70533003-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014431.3(PALD1):​c.803G>A​(p.Arg268His) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,425,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PALD1 NM_014431.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

Genes affected

PALD1 (HGNC:23530): (phosphatase domain containing paladin 1) Predicted to enable protein tyrosine phosphatase activity. Predicted to be involved in peptidyl-tyrosine dephosphorylation. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PALD1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALD1	NM_014431.3	c.803G>A	p.Arg268His	missense_variant	7/20	ENST00000263563.7	NP_055246.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALD1	ENST00000263563.7	c.803G>A	p.Arg268His	missense_variant	7/20	1	NM_014431.3	ENSP00000263563.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425918 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 706222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 29, 2024

The c.803G>A (p.R268H) alteration is located in exon 7 (coding exon 6) of the PALD1 gene. This alteration results from a G to A substitution at nucleotide position 803, causing the arginine (R) at amino acid position 268 to be replaced by a histidine (H). 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	0.25
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.049	D
Polyphen		0.67	P
Vest4		0.84
MutPred		0.87		Gain of relative solvent accessibility (P = 0.1259);
MVP		0.66
MPC		0.42
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.45
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs1480713916; hg19: chr10-72292759;