rs3740447

Variant names:

• chr10-70547345-C-T
• rs3740447
• NM_014431.3:c.2161C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014431.3(PALD1):​c.2161C>T​(p.Arg721Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,612,482 control chromosomes in the GnomAD database, including 22,324 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1846 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20478 hom.)
• Consequence: PALD1 NM_014431.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.375147E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALD1	NM_014431.3	c.2161C>T	p.Arg721Cys	missense_variant	Exon 18 of 20	ENST00000263563.7	NP_055246.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALD1	ENST00000263563.7	c.2161C>T	p.Arg721Cys	missense_variant	Exon 18 of 20	1	NM_014431.3	ENSP00000263563.5

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19970 AN: 151982 Hom.: 1843 Cov.: 32

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.175 AC: 43872 AN: 251150 Hom.: 5107 AF XY: 0.177 AC XY: 24050 AN XY: 135738

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.479

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.156 AC: 227945 AN: 1460380 Hom.: 20478 Cov.: 33 AF XY: 0.158 AC XY: 114512 AN XY: 726616

Gnomad4 AFR exome AF: 0.0309

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.455

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.131 AC: 19980 AN: 152102 Hom.: 1846 Cov.: 32 AF XY: 0.137 AC XY: 10204 AN XY: 74358

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.150

Alfa AF: 0.150 Hom.: 4951

Bravo AF: 0.129

TwinsUK AF: 0.142 AC: 527

ALSPAC AF: 0.152 AC: 587

ESP6500AA AF: 0.0406 AC: 179

ESP6500EA AF: 0.142 AC: 1218

ExAC AF: 0.169 AC: 20464

Asia WGS AF: 0.309 AC: 1072 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.146

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.00054	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.090
MPC		0.27
ClinPred		0.032	T
GERP RS		3.1
Varity_R		0.24
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3740447; hg19: chr10-72307101; COSMIC: COSV54970862;