NM_001352964.2:c.2902C>T

Variant names:

• chr9-123381743-G-A
• rs903159600
• NM_001352964.2:c.2902C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001352964.2(DENND1A):​c.2902C>T​(p.Pro968Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000367 in 1,362,864 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. P968A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: DENND1A NM_001352964.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06599575).

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.2902C>T	p.Pro968Ser	missense	Exon 24 of 24	NP_001339893.1	A0A0A0MS48
	DENND1A	NM_001393654.1		c.2848C>T	p.Pro950Ser	missense	Exon 23 of 23	NP_001380583.1
	DENND1A	NM_001352965.2		c.2752C>T	p.Pro918Ser	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.2902C>T	p.Pro968Ser	missense	Exon 24 of 24	ENSP00000377763.4	A0A0A0MS48
	DENND1A	ENST00000473039.5	TSL:1	n.2711C>T		non_coding_transcript_exon	Exon 18 of 18
	DENND1A	ENST00000866226.1		c.2848C>T	p.Pro950Ser	missense	Exon 23 of 23	ENSP00000536285.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000367 AC: 5 AN: 1362864 Hom.: 0 Cov.: 31 AF XY: 0.00000448 AC XY: 3 AN XY: 669320

African (AFR) AF: 0.00 AC: 0 AN: 30230

American (AMR) AF: 0.00 AC: 0 AN: 29126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22194

East Asian (EAS) AF: 0.00 AC: 0 AN: 35818

South Asian (SAS) AF: 0.00 AC: 0 AN: 72810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 0.00000470 AC: 5 AN: 1063680

Other (OTH) AF: 0.00 AC: 0 AN: 56322

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.024
Sift	Benign	0.15	T
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.062
MutPred		0.15		Gain of phosphorylation at P907 (P = 0.0792)
MVP		0.27
MPC		0.33
ClinPred		0.15	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.26
Mutation Taster		=85/15	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: rs903159600; hg19: chr9-126144022;