Variant 1-197511754-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001195215.2(DENND1B):c.1789A>G(p.Met597Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,608,678 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 11 hom. )

Consequence

DENND1B
NM_001195215.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.19

Variant links:

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]

DENND1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004513949).

BP6

Variant 1-197511754-T-C is Benign according to our data. Variant chr1-197511754-T-C is described in ClinVar as [Benign]. Clinvar id is 712344.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00138 (209/151874) while in subpopulation EAS AF= 0.0275 (141/5136). AF 95% confidence interval is 0.0238. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND1B	NM_001195215.2 linkuse as main transcript	c.1789A>G	p.Met597Val	missense_variant	22/23	ENST00000620048.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND1B	ENST00000620048.6 linkuse as main transcript	c.1789A>G	p.Met597Val	missense_variant	22/23	5	NM_001195215.2	P2	Q6P3S1-1
DENND1B	ENST00000294737.11 linkuse as main transcript	c.*477A>G		3_prime_UTR_variant, NMD_transcript_variant	19/20	2

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

151756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0274

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000737

Gnomad OTH

AF:

0.00480

GnomAD3 exomes

AF:

0.00250

AC:

619

AN:

247750

Hom.:

AF XY:

0.00226

AC XY:

303

AN XY:

133924

show subpopulations

Gnomad AFR exome

AF:

0.000745

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0317

Gnomad SAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.000669

GnomAD4 exome

AF:

0.000751

AC:

1094

AN:

1456804

Hom.:

Cov.:

AF XY:

0.000709

AC XY:

514

AN XY:

724622

show subpopulations

Gnomad4 AFR exome

AF:

0.000602

Gnomad4 AMR exome

AF:

0.000271

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0232

Gnomad4 SAS exome

AF:

0.0000937

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000550

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.00138

AC:

209

AN:

151874

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.000723

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0275

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000738

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.00178

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00232

AC:

282

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000165

EpiControl

AF:

0.000179

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.97

Eigen

Benign

0.054

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.49

Sift4G

Benign

0.39

Vest4

0.33

MVP

0.56

ClinPred

0.013

GERP RS

5.7

Varity_R

0.24

gMVP

0.21

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over