NM_002839.4:c.5031T>A

Variant names:

• chr9-8341185-A-T
• rs12351899
• NM_002839.4:c.5031T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002839.4(PTPRD):​c.5031T>A​(p.Asn1677Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,118 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. Synonymous variant affecting the same amino acid position (i.e. N1677N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTPRD NM_002839.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• Publications: 0 publications found

Genes affected

PTPRD (HGNC:9668): (protein tyrosine phosphatase receptor type D) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular region, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. The extracellular region of this protein is composed of three Ig-like and eight fibronectin type III-like domains. Studies of the similar genes in chicken and fly suggest the role of this PTP is in promoting neurite growth, and regulating neurons axon guidance. Multiple alternatively spliced transcript variants of this gene have been reported. A related pseudogene has been identified on chromosome 5. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRD	NM_002839.4	c.5031T>A	p.Asn1677Lys	missense_variant	Exon 41 of 46	ENST00000381196.9	NP_002830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRD	ENST00000381196.9	c.5031T>A	p.Asn1677Lys	missense_variant	Exon 41 of 46	5	NM_002839.4	ENSP00000370593.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461118 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726870

⚠️ 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: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111518

Other (OTH) AF: 0.00 AC: 0 AN: 60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.;.;D;D;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;M;M;.;.
PhyloP100		2.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.3	D;D;D;.;D;D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D
Polyphen		0.98	D;.;.;D;.;D;D;.;.
Vest4		0.82
MutPred		0.67		Gain of methylation at N1677 (P = 0.0071);.;.;.;.;Gain of methylation at N1677 (P = 0.0071);Gain of methylation at N1677 (P = 0.0071);.;.;
MVP		0.59
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.89
Mutation Taster		=55/45	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: rs12351899; hg19: chr9-8341185;