chr10-119104150-C-A

Variant names:

• chr10-119104150-C-A
• rs368513900
• NM_207009.4:c.8C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207009.4(DENND10):​c.8C>A​(p.Ala3Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000132 in 1,514,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. A3S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: DENND10 NM_207009.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.107252985).

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.8C>A	p.Ala3Glu	missense	Exon 1 of 9	NP_996892.1	Q8TCE6-1
	DENND10	NM_001303111.2		c.-222C>A		5_prime_UTR	Exon 1 of 10	NP_001290040.1	Q8TCE6-2
	DENND10	NM_001303112.2		c.-164C>A		5_prime_UTR	Exon 1 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.8C>A	p.Ala3Glu	missense	Exon 1 of 9	ENSP00000354688.2	Q8TCE6-1
	DENND10	ENST00000857543.1		c.8C>A	p.Ala3Glu	missense	Exon 1 of 9	ENSP00000527602.1
	DENND10	ENST00000857542.1		c.8C>A	p.Ala3Glu	missense	Exon 1 of 8	ENSP00000527601.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151800 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1362806 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 672790

African (AFR) AF: 0.00 AC: 0 AN: 28200

American (AMR) AF: 0.00 AC: 0 AN: 29274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23644

East Asian (EAS) AF: 0.00 AC: 0 AN: 31898

South Asian (SAS) AF: 0.00 AC: 0 AN: 75380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4882

European-Non Finnish (NFE) AF: 9.39e-7 AC: 1 AN: 1064706

Other (OTH) AF: 0.00 AC: 0 AN: 56232

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151800 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74134

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67856

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.37	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.1
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.074
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.034	D
Polyphen		0.32	B
Vest4		0.20
MutPred		0.30		Gain of solvent accessibility (P = 0.0145)
MVP		0.24
MPC		0.38
ClinPred		0.60	D
GERP RS		3.8
PromoterAI		-0.37	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.36
gMVP		0.19
Mutation Taster		=289/11	polymorphism

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

dbSNP: rs368513900; hg19: chr10-120863662;