9-19300284-T-A

Variant names:

• chr9-19300284-T-A
• NM_001330640.2:c.1264T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001330640.2(DENND4C):​c.1264T>A​(p.Ser422Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DENND4C NM_001330640.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4C	NM_001330640.2	c.1264T>A	p.Ser422Thr	missense_variant	Exon 9 of 33	ENST00000434457.7	NP_001317569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4C	ENST00000434457.7	c.1264T>A	p.Ser422Thr	missense_variant	Exon 9 of 33	5	NM_001330640.2	ENSP00000473469.1
DENND4C	ENST00000494124.2	n.580T>A		non_coding_transcript_exon_variant	Exon 5 of 28	1		ENSP00000473273.1
DENND4C	ENST00000602925.5	c.1264T>A	p.Ser422Thr	missense_variant	Exon 9 of 32	5		ENSP00000473565.1
DENND4C	ENST00000380437.8	n.582T>A		non_coding_transcript_exon_variant	Exon 5 of 29	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.556T>A (p.S186T) alteration is located in exon 5 (coding exon 5) of the DENND4C gene. This alteration results from a T to A substitution at nucleotide position 556, causing the serine (S) at amino acid position 186 to be replaced by a threonine (T). 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	0.90
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.58	D
PhyloP100		7.8
PrimateAI	Uncertain	0.77	T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.80
MVP		0.57
MPC		0.26
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.78
Mutation Taster		=28/72	disease causing

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

Other links and lift over

hg19: chr9-19300282;