chr9-123382013-A-G

Position:

• chr9-123382013-A-G

Variant summary

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

The NM_001352964.2(DENND1A):​c.2632T>C​(p.Phe878Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,063,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: DENND1A NM_001352964.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

Genes affected

DENND1A (HGNC:29324): (DENN domain containing 1A) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1A, function as guanine nucleotide exchange factors (GEFs) for the early endosomal small GTPase RAB35 (MIM 604199) and bind to clathrin and clathrin adaptor protein-2 (AP2; see MIM 601024). Thus, connecdenns link RAB35 activation with the clathrin machinery (Marat and McPherson, 2010 [PubMed 20154091]).[supplied by OMIM, Nov 2010]

DENND1A (HGNC:):

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=0.08557996).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND1A	NM_001352964.2	c.2632T>C	p.Phe878Leu	missense_variant	24/24	ENST00000394215.7	NP_001339893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND1A	ENST00000394215.7	c.2632T>C	p.Phe878Leu	missense_variant	24/24	5	NM_001352964.2	ENSP00000377763.4
DENND1A	ENST00000473039.5	n.2441T>C		non_coding_transcript_exon_variant	18/18	1
DENND1A	ENST00000373624.6	c.2449T>C	p.Phe817Leu	missense_variant	22/22	5		ENSP00000362727.2

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000188 AC: 2 AN: 1063104 Hom.: 0 Cov.: 48 AF XY: 0.00000195 AC XY: 1 AN XY: 512188

Gnomad4 AFR exome AF: 0.0000460

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: 0.00000114

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 19

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

Nov 22, 2024

The c.2449T>C (p.F817L) alteration is located in exon 22 (coding exon 22) of the DENND1A gene. This alteration results from a T to C substitution at nucleotide position 2449, causing the phenylalanine (F) at amino acid position 817 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	Uncertain	0.47
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.034
Sift	Benign	0.15	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.28		Loss of catalytic residue at F817 (P = 0.2118);
MVP		0.24
MPC		0.35
ClinPred		0.19	T
GERP RS		3.4
Varity_R		0.099
gMVP		0.29

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: rs2042299066; hg19: chr9-126144292;