Genetic Variant NM_001195215.2:c.547A>G (chr1-197645704-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001195215.2(DENND1B):c.547A>G(p.Thr183Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000664 in 1,566,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T183P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

DENND1B
NM_001195215.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.61

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08127242).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND1B	NM_001195215.2	MANE Select	c.547A>G	p.Thr183Ala	missense	Exon 9 of 23	NP_001182144.1	Q6P3S1-1
DENND1B	NM_144977.5		c.547A>G	p.Thr183Ala	missense	Exon 9 of 16	NP_659414.2	Q6P3S1-5
DENND1B	NM_001300858.2		c.457A>G	p.Thr153Ala	missense	Exon 9 of 16	NP_001287787.1	Q6P3S1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DENND1B	ENST00000620048.6	TSL:5 MANE Select	c.547A>G	p.Thr183Ala	missense	Exon 9 of 23	ENSP00000479816.1	Q6P3S1-1
DENND1B	ENST00000367396.7	TSL:1	c.547A>G	p.Thr183Ala	missense	Exon 9 of 16	ENSP00000356366.3	Q6P3S1-5
DENND1B	ENST00000235453.8	TSL:1	c.457A>G	p.Thr153Ala	missense	Exon 9 of 16	ENSP00000235453.4	Q6P3S1-4

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000950

AC:

AN:

231586

AF XY:

0.0000792

show subpopulations

Gnomad AFR exome

AF:

0.0000692

Gnomad AMR exome

AF:

0.000357

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000758

Gnomad OTH exome

AF:

0.000180

GnomAD4 exome

AF:

0.0000686

AC:

AN:

1414144

Hom.:

Cov.:

AF XY:

0.0000684

AC XY:

AN XY:

701758

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32154

American (AMR)

AF:

0.000366

AC:

AN:

41038

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25208

East Asian (EAS)

AF:

0.00

AC:

AN:

38202

South Asian (SAS)

AF:

0.00

AC:

AN:

74694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51534

Middle Eastern (MID)

AF:

0.000188

AC:

AN:

5306

European-Non Finnish (NFE)

AF:

0.0000653

AC:

AN:

1087842

Other (OTH)

AF:

0.000155

AC:

AN:

58166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41534

American (AMR)

AF:

0.000196

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67816

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.596

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000660

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000497

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.018

MetaRNN

Benign

0.081

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

4.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.8

REVEL

Benign

0.13

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0050

Polyphen

0.39

Vest4

0.77

MVP

0.19

MPC

0.18

ClinPred

0.070

GERP RS

5.4

Varity_R

0.40

gMVP

0.58

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over