6-30894620-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001297654.2(DDR1):c.1462C>T(p.Arg488Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,612,488 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (4 hom.)
• Consequence: DDR1 NM_001297654.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.68

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020066202).
• BP6: Variant 6-30894620-C-T is Benign according to our data. Variant chr6-30894620-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 731325.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDR1	NM_001297654.2	c.1462C>T	p.Arg488Trp	missense_variant	11/18	ENST00000376568.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDR1	ENST00000376568.8	c.1462C>T	p.Arg488Trp	missense_variant	11/18	1	NM_001297654.2	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152138 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.000417 AC: 104 AN: 249522 Hom.: 3 AF XY: 0.000334 AC XY: 45 AN XY: 134892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1460350 Hom.: 4 Cov.: 31 AF XY: 0.0000950 AC XY: 69 AN XY: 726498

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00312

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152138 Hom.: 1 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74304

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000916

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

Alfa AF: 0.0000980 Hom.: 0

Bravo AF: 0.000291

ExAC AF: 0.000321 AC: 39

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;.;.;.;.;T;T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.020	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.12	T;T;T;T;T;T;T;D;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;D;D;.;.;D
Vest4		0.47
MutPred		0.28		Gain of catalytic residue at R488 (P = 0.0121);Gain of catalytic residue at R488 (P = 0.0121);Gain of catalytic residue at R488 (P = 0.0121);Gain of catalytic residue at R488 (P = 0.0121);Gain of catalytic residue at R488 (P = 0.0121);Gain of catalytic residue at R488 (P = 0.0121);Gain of catalytic residue at R488 (P = 0.0121);.;Gain of catalytic residue at R488 (P = 0.0121);Gain of catalytic residue at R488 (P = 0.0121);
MVP		0.91
ClinPred		0.11	T
GERP RS		5.2
Varity_R		0.20
gMVP		0.45

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: rs775463181; hg19: chr6-30862397;