6-30893115-G-C

Position:

• chr6-30893115-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001297654.2(DDR1):​c.1147G>C​(p.Ala383Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DDR1 NM_001297654.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26801467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDR1	NM_001297654.2	c.1147G>C	p.Ala383Pro	missense_variant	9/18	ENST00000376568.8	NP_001284583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDR1	ENST00000376568.8	c.1147G>C	p.Ala383Pro	missense_variant	9/18	1	NM_001297654.2	ENSP00000365752.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459232 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.1147G>C (p.A383P) alteration is located in exon 8 (coding exon 8) of the DDR1 gene. This alteration results from a G to C substitution at nucleotide position 1147, causing the alanine (A) at amino acid position 383 to be replaced by a proline (P). 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	Benign	0.083
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;.;.;.;.;T;T;.;.;T;.;T
Eigen	Benign	-0.061
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	.;.;.;.;.;.;.;.;.;.;T;.
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	-0.23	N;N;N;N;N;N;N;.;N;.;N;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.24	N;N;N;N;N;N;N;N;N;.;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.11	T;T;T;T;T;T;T;T;T;.;T;T
Sift4G	Benign	0.44	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0060	B;.;.;.;.;B;B;.;.;.;B;B
Vest4		0.49
MutPred		0.27		Gain of glycosylation at A383 (P = 0.0012);Gain of glycosylation at A383 (P = 0.0012);Gain of glycosylation at A383 (P = 0.0012);Gain of glycosylation at A383 (P = 0.0012);Gain of glycosylation at A383 (P = 0.0012);Gain of glycosylation at A383 (P = 0.0012);Gain of glycosylation at A383 (P = 0.0012);.;Gain of glycosylation at A383 (P = 0.0012);Gain of glycosylation at A383 (P = 0.0012);Gain of glycosylation at A383 (P = 0.0012);.;
MVP		0.87
ClinPred		0.56	D
GERP RS		4.6
Varity_R		0.21
gMVP		0.50

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: rs1416694443; hg19: chr6-30860892;