11-104036945-C-T

Position:

• chr11-104036945-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001001711.3(DDI1):​c.123C>T​(p.Pro41=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,614,198 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (18 hom.)
• Consequence: DDI1 NM_001001711.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.58

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00266549).
• BP6: Variant 11-104036945-C-T is Benign according to our data. Variant chr11-104036945-C-T is described in ClinVar as [Benign]. Clinvar id is 770220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00402 (613/152314) while in subpopulation AMR AF= 0.0336 (515/15306). AF 95% confidence interval is 0.0312. There are 19 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDI1	NM_001001711.3	c.123C>T	p.Pro41=	synonymous_variant	1/1	ENST00000302259.5
PDGFD	NM_025208.5	c.125-36690G>A		intron_variant		ENST00000393158.7
PDGFD	NM_033135.4	c.125-36708G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDI1	ENST00000302259.5	c.123C>T	p.Pro41=	synonymous_variant	1/1		NM_001001711.3	P1
PDGFD	ENST00000393158.7	c.125-36690G>A		intron_variant		1	NM_025208.5	P1
PDGFD	ENST00000302251.9	c.125-36708G>A		intron_variant		1
PDGFD	ENST00000529268.1	c.82G>A	p.Gly28Arg	missense_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 612 AN: 152196 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0336

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00334 AC: 841 AN: 251478 Hom.: 11 AF XY: 0.00254 AC XY: 345 AN XY: 135918

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0212

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00116 AC: 1696 AN: 1461884 Hom.: 18 Cov.: 30 AF XY: 0.00106 AC XY: 772 AN XY: 727246

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000545

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00402 AC: 613 AN: 152314 Hom.: 19 Cov.: 32 AF XY: 0.00495 AC XY: 369 AN XY: 74482

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.0336

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000762 Hom.: 0

Bravo AF: 0.00512

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.041
DANN	Benign	0.69
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.026
Sift	Uncertain	0.0030	D
MutPred		0.45		Loss of catalytic residue at G28 (P = 8e-04);
MVP		0.092
ClinPred		0.017	T
GERP RS		-9.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs138352725; hg19: chr11-103907673; COSMIC: COSV100160047;