6-30889416-C-T

Position:

chr6-30889416-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001297654.2(DDR1):c.403C>T(p.Arg135Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000135 in 1,554,406 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: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

DDR1
NM_001297654.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.11

Variant links:

Genes affected

DDR1 (HGNC:2730): (discoidin domain receptor tyrosine kinase 1) Receptor tyrosine kinases play a key role in the communication of cells with their microenvironment. These kinases are involved in the regulation of cell growth, differentiation and metabolism. The protein encoded by this gene belongs to a subfamily of tyrosine kinase receptors with homology to Dictyostelium discoideum protein discoidin I in their extracellular domain, and that are activated by various types of collagen. Expression of this protein is restricted to epithelial cells, particularly in the kidney, lung, gastrointestinal tract, and brain. In addition, it has been shown to be significantly overexpressed in several human tumors. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2011]

DDR1 links:

DDR1 (HGNC:):

DDR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDR1	NM_001297654.2 linkuse as main transcript	c.403C>T	p.Arg135Cys	missense_variant	4/18	ENST00000376568.8	NP_001284583.1	Q08345-1A0A024RCL1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDR1	ENST00000376568.8 linkuse as main transcript	c.403C>T	p.Arg135Cys	missense_variant	4/18	1	NM_001297654.2	ENSP00000365752.3		Q08345-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000115

AC:

AN:

174182

Hom.:

AF XY:

0.0000107

AC XY:

AN XY:

93654

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000520

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000998

AC:

AN:

1402150

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

690806

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000261

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000831

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000344

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2024

The c.403C>T (p.R135C) alteration is located in exon 3 (coding exon 3) of the DDR1 gene. This alteration results from a C to T substitution at nucleotide position 403, causing the arginine (R) at amino acid position 135 to be replaced by a cysteine (C). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

D;D;.;D;.;D;.;D;D;.;.;D;D;D;D;.;D;D;.;.;T;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.;.;D;.;.;D;.;D;.;.;D;D;.;.;.;.;D;D;.;.;.;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

.;M;M;.;M;.;.;.;.;M;M;.;.;M;M;.;.;.;.;M;.;M;M

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-6.3

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.043

D;D;D;T;D;T;T;D;D;D;D;T;T;D;D;D;T;D;T;D;D;T;D

Polyphen

1.0

.;D;.;.;.;.;.;.;.;.;.;.;.;D;D;.;.;.;.;.;.;D;D

Vest4

0.80, 0.63, 0.71, 0.62, 0.57, 0.80, 0.80, 0.74, 0.62, 0.72, 0.58, 0.79

MutPred

0.54

Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);.;Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);.;Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);Gain of catalytic residue at W136 (P = 9e-04);

MVP

0.92

MPC

1.6

ClinPred

0.95

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.65

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over