11-104037022-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001711.3(DDI1):c.200A>G(p.Lys67Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDI1 NM_001001711.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

Genes affected

DDI1 (HGNC:18961): (DNA damage inducible 1 homolog 1) Predicted to enable aspartic-type endopeptidase activity. Involved in several processes, including cellular response to hydroxyurea; proteasomal protein catabolic process; and regulation of DNA stability. [provided by Alliance of Genome Resources, Apr 2022]

PDGFD (HGNC:30620): (platelet derived growth factor D) The protein encoded by this gene is a member of the platelet-derived growth factor family. The four members of this family are mitogenic factors for cells of mesenchymal origin and are characterized by a core motif of eight cysteines, seven of which are found in this factor. This gene product only forms homodimers and, therefore, does not dimerize with the other three family members. It differs from alpha and beta members of this family in having an unusual N-terminal domain, the CUB domain. Two splice variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13029853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDI1	NM_001001711.3	c.200A>G	p.Lys67Arg	missense_variant	1/1	ENST00000302259.5
PDGFD	NM_025208.5	c.125-36767T>C		intron_variant		ENST00000393158.7
PDGFD	NM_033135.4	c.125-36785T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDI1	ENST00000302259.5	c.200A>G	p.Lys67Arg	missense_variant	1/1		NM_001001711.3	P1
PDGFD	ENST00000393158.7	c.125-36767T>C		intron_variant		1	NM_025208.5	P1
PDGFD	ENST00000302251.9	c.125-36785T>C		intron_variant		1
PDGFD	ENST00000529268.1	c.5T>C	p.Phe2Ser	missense_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jul 20, 2021

The c.200A>G (p.K67R) alteration is located in exon 1 (coding exon 1) of the DDI1 gene. This alteration results from a A to G substitution at nucleotide position 200, causing the lysine (K) at amino acid position 67 to be replaced by an arginine (R). 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	0.070
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	16
Dann	Uncertain	0.98
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	1.5	N
REVEL	Benign	0.073
Sift	Pathogenic	0.0	D
MutPred		0.54		Gain of disorder (P = 0.0125);
MVP		0.28
ClinPred		0.39	T
GERP RS		0.079

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-103907750;