1-111188226-G-A

Position:

• chr1-111188226-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024901.5(DENND2D):​c.1244C>T​(p.Ser415Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND2D NM_024901.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38

Genes affected

DENND2D (HGNC:26192): (DENN domain containing 2D) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DENND2D (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2D	NM_024901.5	c.1244C>T	p.Ser415Phe	missense_variant	11/12	ENST00000357640.9	NP_079177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2D	ENST00000357640.9	c.1244C>T	p.Ser415Phe	missense_variant	11/12	1	NM_024901.5	ENSP00000350266.4
DENND2D	ENST00000369752.5	c.1235C>T	p.Ser412Phe	missense_variant	11/12	2		ENSP00000358767.5
DENND2D	ENST00000468692.1	n.347C>T		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

May 15, 2024

The c.1244C>T (p.S415F) alteration is located in exon 11 (coding exon 11) of the DENND2D gene. This alteration results from a C to T substitution at nucleotide position 1244, causing the serine (S) at amino acid position 415 to be replaced by a phenylalanine (F). 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	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.72
MutPred		0.78		Gain of methylation at K416 (P = 0.0287);.;
MVP		0.66
MPC		1.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.86
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-111730848;