10-119108016-C-T

Variant names:

• chr10-119108016-C-T
• rs942250644
• NM_207009.4:c.104C>T

Variant summary

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

The NM_001303112.2(DENND10):​c.-48C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DENND10 NM_001303112.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47
• 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=0.26050028).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303112.2. 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.104C>T	p.Thr35Met	missense	Exon 2 of 9	NP_996892.1	Q8TCE6-1
	DENND10	NM_001303112.2		c.-48C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001290041.1	B4DNL9
	DENND10	NM_001303113.2		c.-201C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001290042.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND10	ENST00000361432.3	TSL:1 MANE Select	c.104C>T	p.Thr35Met	missense	Exon 2 of 9	ENSP00000354688.2	Q8TCE6-1
	DENND10	ENST00000648560.1		c.-352C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 12	ENSP00000496780.1	A0A3B3IRE4
	DENND10	ENST00000857543.1		c.104C>T	p.Thr35Met	missense	Exon 2 of 9	ENSP00000527602.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251486 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461586 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727114

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.0000656 AC: 1 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0066	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.5
PROVEAN	Benign	0.38	N
REVEL	Benign	0.10
Sift	Benign	0.11	T
Sift4G	Uncertain	0.031	D
Polyphen		0.96	D
Vest4		0.33
MutPred		0.33		Loss of catalytic residue at T35 (P = 0.0225)
MVP		0.60
MPC		0.71
ClinPred		0.55	D
GERP RS		6.0
Varity_R		0.042
gMVP		0.24
Mutation Taster		=278/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs942250644; hg19: chr10-120867528; COSMIC: COSV100813968; COSMIC: COSV100813968;