10-119129581-A-G

Position:

• chr10-119129581-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000361432.3(DENND10):​c.761A>G​(p.Asn254Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DENND10 ENST00000361432.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND10	NM_207009.4	c.761A>G	p.Asn254Ser	missense_variant	7/9	ENST00000361432.3	NP_996892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND10	ENST00000361432.3	c.761A>G	p.Asn254Ser	missense_variant	7/9	1	NM_207009.4	ENSP00000354688	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251466 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135908

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461386 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.761A>G (p.N254S) alteration is located in exon 7 (coding exon 7) of the FAM45A gene. This alteration results from a A to G substitution at nucleotide position 761, causing the asparagine (N) at amino acid position 254 to be replaced by a serine (S). 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	Benign	0.11
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Uncertain	-3.7	D;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		1.0	D;.
Vest4		0.56
MutPred		0.45		Gain of glycosylation at N254 (P = 0.0955);.;
MVP		0.57
MPC		0.75
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.39
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1360965126; hg19: chr10-120889093;