Genetic Variant NM_001330640.2:c.1121A>T (chr9-19299242-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001330640.2(DENND4C):c.1121A>T(p.Asp374Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DENND4C
NM_001330640.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.35

Publications

0 publications found

Variant links:

Genes affected

DENND4C (HGNC:26079): (DENN domain containing 4C) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in cellular response to insulin stimulus; protein localization to plasma membrane; and regulation of Rab protein signal transduction. Located in Golgi apparatus and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

DENND4C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4C	NM_001330640.2 link	c.1121A>T	p.Asp374Val	missense_variant	Exon 8 of 33	ENST00000434457.7	NP_001317569.1	Q5VZ89-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DENND4C	ENST00000434457.7 link	c.1121A>T	p.Asp374Val	missense_variant	Exon 8 of 33	5	NM_001330640.2	ENSP00000473469.1	Q5VZ89-7
DENND4C	ENST00000494124.2 link	n.437A>T		non_coding_transcript_exon_variant	Exon 4 of 28	1		ENSP00000473273.1	R4GMN2
DENND4C	ENST00000602925.5 link	c.1121A>T	p.Asp374Val	missense_variant	Exon 8 of 32	5		ENSP00000473565.1	Q5VZ89-1
DENND4C	ENST00000380437.8 link	n.439A>T		non_coding_transcript_exon_variant	Exon 4 of 29	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

149468

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1427160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709140

African (AFR)

AF:

0.00

AC:

AN:

31432

American (AMR)

AF:

0.00

AC:

AN:

38850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25526

East Asian (EAS)

AF:

0.00

AC:

AN:

38780

South Asian (SAS)

AF:

0.00

AC:

AN:

78042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097030

Other (OTH)

AF:

0.00

AC:

AN:

58984

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

149468

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72708

African (AFR)

AF:

0.00

AC:

AN:

40590

American (AMR)

AF:

0.00

AC:

AN:

14982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67502

Other (OTH)

AF:

0.00

AC:

AN:

2058

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 23, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.413A>T (p.D138V) alteration is located in exon 4 (coding exon 4) of the DENND4C gene. This alteration results from a A to T substitution at nucleotide position 413, causing the aspartic acid (D) at amino acid position 138 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

0.031

PhyloP100

8.3

PrimateAI

Uncertain

0.75

Sift4G

Uncertain

0.0030

D;D

Vest4

0.80

MVP

0.45

MPC

0.27

ClinPred

0.99

GERP RS

4.1

Varity_R

0.57

gMVP

0.69

Mutation Taster

=38/62

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over