rs34764696

Positions:

• chr6-43144529-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002821.5(PTK7):​c.2330C>T​(p.Ala777Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,614,106 control chromosomes in the GnomAD database, including 3,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.054 (239 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3410 hom.)
• Consequence: PTK7 NM_002821.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.19

Genes affected

PTK7 (HGNC:9618): (protein tyrosine kinase 7 (inactive)) This gene encodes a member of the receptor protein tyrosine kinase family of proteins that transduce extracellular signals across the cell membrane. The encoded protein lacks detectable catalytic tyrosine kinase activity, is involved in the Wnt signaling pathway and plays a role in multiple cellular processes including polarity and adhesion. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002228111).
• BP6: Variant 6-43144529-C-T is Benign according to our data. Variant chr6-43144529-C-T is described in ClinVar as [Benign]. Clinvar id is 3060982.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTK7	NM_002821.5	c.2330C>T	p.Ala777Val	missense_variant	15/20	ENST00000230419.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTK7	ENST00000230419.9	c.2330C>T	p.Ala777Val	missense_variant	15/20	1	NM_002821.5	P1

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 8205 AN: 152186 Hom.: 238 Cov.: 33

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00807

Gnomad SAS AF: 0.0396

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0693

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0468 AC: 11762 AN: 251360 Hom.: 343 AF XY: 0.0486 AC XY: 6599 AN XY: 135864

Gnomad AFR exome AF: 0.0437

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.00620

Gnomad SAS exome AF: 0.0422

Gnomad FIN exome AF: 0.0457

Gnomad NFE exome AF: 0.0648

Gnomad OTH exome AF: 0.0491

GnomAD4 exome AF: 0.0654 AC: 95608 AN: 1461802 Hom.: 3410 Cov.: 31 AF XY: 0.0647 AC XY: 47055 AN XY: 727218

Gnomad4 AFR exome AF: 0.0456

Gnomad4 AMR exome AF: 0.0242

Gnomad4 ASJ exome AF: 0.0228

Gnomad4 EAS exome AF: 0.00912

Gnomad4 SAS exome AF: 0.0430

Gnomad4 FIN exome AF: 0.0485

Gnomad4 NFE exome AF: 0.0739

Gnomad4 OTH exome AF: 0.0565

GnomAD4 genome AF: 0.0540 AC: 8223 AN: 152304 Hom.: 239 Cov.: 33 AF XY: 0.0520 AC XY: 3870 AN XY: 74478

Gnomad4 AFR AF: 0.0476

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00809

Gnomad4 SAS AF: 0.0392

Gnomad4 FIN AF: 0.0455

Gnomad4 NFE AF: 0.0693

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0628 Hom.: 510

Bravo AF: 0.0532

TwinsUK AF: 0.0742 AC: 275

ALSPAC AF: 0.0615 AC: 237

ESP6500AA AF: 0.0433 AC: 191

ESP6500EA AF: 0.0702 AC: 604

ExAC AF: 0.0477 AC: 5789

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0645

EpiControl AF: 0.0597

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PTK7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T;.;.;.;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.84	T;T;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.81	L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.11	T;T;T;D;T;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		0.15	B;B;B;B;.;.
Vest4		0.21
MPC		0.25
ClinPred		0.011	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.22

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: rs34764696; hg19: chr6-43112267; COSMIC: COSV57851025; COSMIC: COSV57851025;