10-70529300-C-G

Variant names:

• chr10-70529300-C-G
• rs371124402
• NM_014431.3:c.257C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_014431.3(PALD1):​c.257C>G​(p.Ser86Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000347 in 1,442,190 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S86L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PALD1 NM_014431.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.74
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity PALD_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014431.3. 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
	PALD1	NM_014431.3	MANE Select	c.257C>G	p.Ser86Trp	missense	Exon 3 of 20	NP_055246.2	Q9ULE6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALD1	ENST00000263563.7	TSL:1 MANE Select	c.257C>G	p.Ser86Trp	missense	Exon 3 of 20	ENSP00000263563.5	Q9ULE6
	PALD1	ENST00000697571.1		c.257C>G	p.Ser86Trp	missense	Exon 3 of 21	ENSP00000513342.1	A0A8V8TMP9
	PALD1	ENST00000893833.1		c.257C>G	p.Ser86Trp	missense	Exon 4 of 21	ENSP00000563892.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1442190 Hom.: 0 Cov.: 30 AF XY: 0.00000418 AC XY: 3 AN XY: 717192

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33102

American (AMR) AF: 0.00 AC: 0 AN: 44024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 38872

South Asian (SAS) AF: 0.00 AC: 0 AN: 85112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00000455 AC: 5 AN: 1098766

Other (OTH) AF: 0.00 AC: 0 AN: 59296

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

Alfa AF: 0.0000226 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.40		Loss of disorder (P = 1e-04)
MVP		0.81
MPC		0.89
ClinPred		0.95	D
GERP RS		4.1
Varity_R		0.37
gMVP		0.79
Mutation Taster		=74/26	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: rs371124402; hg19: chr10-72289056;