10-119123483-T-C

Variant names:

• chr10-119123483-T-C
• NM_207009.4:c.608T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_207009.4(DENND10):​c.608T>C​(p.Leu203Pro) variant causes a missense change. 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: 32)
• Consequence: DENND10 NM_207009.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.61
• Publications: 0 publications found

Genes affected

DENND10 (HGNC:31793): (DENN domain containing 10) Enables guanyl-nucleotide exchange factor activity and small GTPase binding activity. Involved in endosome transport via multivesicular body sorting pathway; protein transport; and regulation of early endosome to late endosome transport. Located in late endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207009.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND10	NM_207009.4	MANE Select	c.608T>C	p.Leu203Pro	missense	Exon 6 of 9	NP_996892.1	Q8TCE6-1
	DENND10	NM_001303111.2		c.584T>C	p.Leu195Pro	missense	Exon 7 of 10	NP_001290040.1	Q8TCE6-2
	DENND10	NM_001303112.2		c.389T>C	p.Leu130Pro	missense	Exon 6 of 9	NP_001290041.1	B4DNL9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND10	ENST00000361432.3	TSL:1 MANE Select	c.608T>C	p.Leu203Pro	missense	Exon 6 of 9	ENSP00000354688.2	Q8TCE6-1
	DENND10	ENST00000857543.1		c.563T>C	p.Leu188Pro	missense	Exon 6 of 9	ENSP00000527602.1
	DENND10	ENST00000857542.1		c.608T>C	p.Leu203Pro	missense	Exon 6 of 8	ENSP00000527601.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.6
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.66		Loss of catalytic residue at L203 (P = 0.0028)
MVP		0.64
MPC		1.4
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.83
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr10-120882995;