9-123381911-G-C

Variant names:

• chr9-123381911-G-C
• rs374521148
• NM_001352964.2:c.2734C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001352964.2(DENND1A):​c.2734C>G​(p.Pro912Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000078 in 1,281,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P912T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000078 (0 hom.)
• Consequence: DENND1A NM_001352964.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.985
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.092247635).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352964.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1A	NM_001352964.2	MANE Select	c.2734C>G	p.Pro912Ala	missense	Exon 24 of 24	NP_001339893.1	A0A0A0MS48
	DENND1A	NM_001393654.1		c.2680C>G	p.Pro894Ala	missense	Exon 23 of 23	NP_001380583.1
	DENND1A	NM_001352965.2		c.2584C>G	p.Pro862Ala	missense	Exon 21 of 21	NP_001339894.1	Q8TEH3-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1A	ENST00000394215.7	TSL:5 MANE Select	c.2734C>G	p.Pro912Ala	missense	Exon 24 of 24	ENSP00000377763.4	A0A0A0MS48
	DENND1A	ENST00000473039.5	TSL:1	n.2543C>G		non_coding_transcript_exon	Exon 18 of 18
	DENND1A	ENST00000866226.1		c.2680C>G	p.Pro894Ala	missense	Exon 23 of 23	ENSP00000536285.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000780 AC: 10 AN: 1281910 Hom.: 0 Cov.: 55 AF XY: 0.00000965 AC XY: 6 AN XY: 621998

African (AFR) AF: 0.00 AC: 0 AN: 28534

American (AMR) AF: 0.00 AC: 0 AN: 19210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18522

East Asian (EAS) AF: 0.00 AC: 0 AN: 35288

South Asian (SAS) AF: 0.00 AC: 0 AN: 63220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3910

European-Non Finnish (NFE) AF: 0.00000885 AC: 9 AN: 1016662

Other (OTH) AF: 0.0000190 AC: 1 AN: 52734

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.2
DANN	Benign	0.47
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.98
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.021
Sift	Benign	0.072	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.22		Loss of phosphorylation at T850 (P = 0.0723)
MVP		0.20
MPC		0.29
ClinPred		0.062	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.032
gMVP		0.21
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs374521148; hg19: chr9-126144190;