Genetic Variant DENND1A:c.1543-970G>A (chr9-123404460-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001352964.2(DENND1A):c.1543-970G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,196 control chromosomes in the GnomAD database, including 3,122 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 3122 hom., cov: 32)

Consequence

DENND1A
NM_001352964.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.19

Publications

4 publications found

Variant links:

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]

DENND1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DENND1A	NM_001352964.2	MANE Select	c.1543-970G>A	intron	N/A	NP_001339893.1	A0A0A0MS48
DENND1A	NM_001393654.1		c.1489-970G>A	intron	N/A	NP_001380583.1
DENND1A	NM_001352965.2		c.1393-970G>A	intron	N/A	NP_001339894.1	Q8TEH3-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DENND1A	ENST00000394215.7	TSL:5 MANE Select	c.1543-970G>A	intron	N/A	ENSP00000377763.4	A0A0A0MS48
DENND1A	ENST00000373620.7	TSL:1	c.1489-970G>A	intron	N/A	ENSP00000362722.3	Q8TEH3-2
DENND1A	ENST00000473039.5	TSL:1	n.1352-970G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.185

AC:

28067

AN:

152078

Hom.:

3111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.308

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.0631

Gnomad EAS

AF:

0.0929

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.125

Gnomad OTH

AF:

0.177

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.185

AC:

28118

AN:

152196

Hom.:

3122

Cov.:

AF XY:

0.187

AC XY:

13928

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.308

AC:

12758

AN:

41482

American (AMR)

AF:

0.195

AC:

2979

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0631

AC:

219

AN:

3472

East Asian (EAS)

AF:

0.0925

AC:

480

AN:

5188

South Asian (SAS)

AF:

0.133

AC:

644

AN:

4824

European-Finnish (FIN)

AF:

0.191

AC:

2028

AN:

10594

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.125

AC:

8480

AN:

68016

Other (OTH)

AF:

0.175

AC:

369

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1140

2280

3421

4561

5701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

288

576

864

1152

1440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.133

Hom.:

2681

Bravo

AF:

0.192

Asia WGS

AF:

0.101

AC:

351

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.13

(source)

DANN

Benign

0.65

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over