NM_001195215.2:c.1184G>A

Variant names:

• chr1-197553078-C-T
• rs759209652
• NM_001195215.2:c.1184G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001195215.2(DENND1B):​c.1184G>A​(p.Gly395Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000718 in 1,393,670 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DENND1B NM_001195215.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15
• Publications: 0 publications found

Genes affected

DENND1B (HGNC:28404): (DENN domain containing 1B) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1B, 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195215.2. 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
	DENND1B	NM_001195215.2	MANE Select	c.1184G>A	p.Gly395Glu	missense	Exon 16 of 23	NP_001182144.1	Q6P3S1-1
	DENND1B	NM_144977.5		c.1184G>A	p.Gly395Glu	missense	Exon 16 of 16	NP_659414.2	Q6P3S1-5
	DENND1B	NM_001300858.2		c.1094G>A	p.Gly365Glu	missense	Exon 16 of 16	NP_001287787.1	Q6P3S1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1B	ENST00000620048.6	TSL:5 MANE Select	c.1184G>A	p.Gly395Glu	missense	Exon 16 of 23	ENSP00000479816.1	Q6P3S1-1
	DENND1B	ENST00000367396.7	TSL:1	c.1184G>A	p.Gly395Glu	missense	Exon 16 of 16	ENSP00000356366.3	Q6P3S1-5
	DENND1B	ENST00000235453.8	TSL:1	c.1094G>A	p.Gly365Glu	missense	Exon 16 of 16	ENSP00000235453.4	Q6P3S1-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000523 AC: 1 AN: 191296 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000813

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393670 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691364

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29346

American (AMR) AF: 0.00 AC: 0 AN: 30058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24280

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35696

South Asian (SAS) AF: 0.00 AC: 0 AN: 73432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085184

Other (OTH) AF: 0.00 AC: 0 AN: 57610

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.079	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.46		Gain of solvent accessibility (P = 0.024)
MVP		0.75
MPC		0.34
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.67
gMVP		0.69
Mutation Taster		=29/71	disease causing

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: rs759209652; hg19: chr1-197522208;