rs554571516

Variant names:

• chr1-197595329-G-A
• rs554571516
• NM_001195215.2:c.926C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001195215.2(DENND1B):​c.926C>T​(p.Ser309Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,612,248 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: DENND1B NM_001195215.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23447493).

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.926C>T	p.Ser309Leu	missense	Exon 14 of 23	NP_001182144.1	Q6P3S1-1
	DENND1B	NM_144977.5		c.926C>T	p.Ser309Leu	missense	Exon 14 of 16	NP_659414.2	Q6P3S1-5
	DENND1B	NM_001300858.2		c.836C>T	p.Ser279Leu	missense	Exon 14 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.926C>T	p.Ser309Leu	missense	Exon 14 of 23	ENSP00000479816.1	Q6P3S1-1
	DENND1B	ENST00000367396.7	TSL:1	c.926C>T	p.Ser309Leu	missense	Exon 14 of 16	ENSP00000356366.3	Q6P3S1-5
	DENND1B	ENST00000235453.8	TSL:1	c.836C>T	p.Ser279Leu	missense	Exon 14 of 16	ENSP00000235453.4	Q6P3S1-4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000725 AC: 18 AN: 248178 AF XY: 0.0000669

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000837

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1460166 Hom.: 1 Cov.: 30 AF XY: 0.000113 AC XY: 82 AN XY: 726386

African (AFR) AF: 0.0000599 AC: 2 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.000429 AC: 17 AN: 39668

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1110910

Other (OTH) AF: 0.0000995 AC: 6 AN: 60318

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000778 AC: 4 AN: 5144

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000828 AC: 10

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	0.087
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.026	D
Polyphen		0.033	B
Vest4		0.81
MutPred		0.46		Loss of disorder (P = 0.0149)
MVP		0.10
MPC		0.042
ClinPred		0.51	D
GERP RS		6.1
Varity_R		0.75
gMVP		0.55
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs554571516; hg19: chr1-197564459;