9-123381911-G-T

Variant names:

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

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.2734C>A​(p.Pro912Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,430,736 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: DENND1A NM_001352964.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: 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=0.0049282014).

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>A	p.Pro912Thr	missense	Exon 24 of 24	NP_001339893.1	A0A0A0MS48
	DENND1A	NM_001393654.1		c.2680C>A	p.Pro894Thr	missense	Exon 23 of 23	NP_001380583.1
	DENND1A	NM_001352965.2		c.2584C>A	p.Pro862Thr	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>A	p.Pro912Thr	missense	Exon 24 of 24	ENSP00000377763.4	A0A0A0MS48
	DENND1A	ENST00000473039.5	TSL:1	n.2543C>A		non_coding_transcript_exon	Exon 18 of 18
	DENND1A	ENST00000866226.1		c.2680C>A	p.Pro894Thr	missense	Exon 23 of 23	ENSP00000536285.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 43 AN: 148830 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.0102

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000747

Gnomad OTH AF: 0.000488

GnomAD2 exomes AF: 0.000248 AC: 20 AN: 80520 AF XY: 0.0000996

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000190

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000628

Gnomad OTH exome AF: 0.000897

GnomAD4 exome AF: 0.000202 AC: 259 AN: 1281906 Hom.: 1 Cov.: 55 AF XY: 0.000211 AC XY: 131 AN XY: 621994

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

American (AMR) AF: 0.000208 AC: 4 AN: 19210

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 176 AN: 18522

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

South Asian (SAS) AF: 0.0000316 AC: 2 AN: 63220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43828

Middle Eastern (MID) AF: 0.000256 AC: 1 AN: 3910

European-Non Finnish (NFE) AF: 0.0000423 AC: 43 AN: 1016660

Other (OTH) AF: 0.000626 AC: 33 AN: 52734

GnomAD4 genome AF: 0.000289 AC: 43 AN: 148830 Hom.: 0 Cov.: 26 AF XY: 0.000276 AC XY: 20 AN XY: 72548

African (AFR) AF: 0.00 AC: 0 AN: 40646

American (AMR) AF: 0.000133 AC: 2 AN: 15020

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 35 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 4908

South Asian (SAS) AF: 0.00 AC: 0 AN: 4586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000747 AC: 5 AN: 66952

Other (OTH) AF: 0.000488 AC: 1 AN: 2050

Alfa AF: 0.000371 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000387 AC: 3

ExAC AF: 0.000156 AC: 15

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.8
DANN	Benign	0.85
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.98
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.023
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.054	T
Polyphen		0.039	B
Vest4		0.12
MVP		0.19
MPC		0.34
ClinPred		0.058	T
GERP RS		-2.6
Varity_R		0.060
gMVP		0.29
Mutation Taster		=87/13	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;