12-48999125-T-A

Variant names:

• chr12-48999125-T-A
• rs774638950
• NM_015086.2:c.163A>T

Variant summary

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

The NM_015086.2(DDN):​c.163A>T​(p.Met55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DDN NM_015086.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

Genes affected

DDN (HGNC:24458): (dendrin) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to act upstream of or within positive regulation of transcription by RNA polymerase II. Located in cell projection and cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DDN-AS1 (HGNC:53464): (DDN and PRKAG1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDN	NM_015086.2	c.163A>T	p.Met55Leu	missense_variant	Exon 1 of 2	ENST00000421952.3	NP_055901.2
DDN-AS1	NR_147178.1	n.344+435T>A		intron_variant	Intron 1 of 2
DDN-AS1	NR_147179.1	n.344+435T>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDN	ENST00000421952.3	c.163A>T	p.Met55Leu	missense_variant	Exon 1 of 2	1	NM_015086.2	ENSP00000390590.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727230

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.163A>T (p.M55L) alteration is located in exon 1 (coding exon 1) of the DDN gene. This alteration results from a A to T substitution at nucleotide position 163, causing the methionine (M) at amino acid position 55 to be replaced by a leucine (L). 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	0.25
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.47	T
Polyphen		0.80	P
Vest4		0.53
MutPred		0.26		Loss of MoRF binding (P = 0.0796);
MVP		0.45
MPC		1.5
ClinPred		0.96	D
GERP RS		3.7
Varity_R		0.82
gMVP		0.066

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: rs774638950; hg19: chr12-49392908;