9-37801135-C-G

Variant names:

• chr9-37801135-C-G
• rs1017451713
• NM_024345.5:c.269C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_024345.5(DCAF10):​c.269C>G​(p.Pro90Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000911 in 1,536,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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: 0.0000094 (0 hom.)
• Consequence: DCAF10 NM_024345.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.290
• Publications: 0 publications found

Genes affected

DCAF10 (HGNC:23686): (DDB1 and CUL4 associated factor 10) Predicted to be involved in protein ubiquitination. Part of Cul4-RING E3 ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255872 (HGNC:):

EXOSC3 (HGNC:17944): (exosome component 3) This gene encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2012]

EXOSC3 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12742984).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024345.5. 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
	DCAF10	NM_024345.5	MANE Select	c.269C>G	p.Pro90Arg	missense	Exon 1 of 7	NP_077321.3
	DCAF10	NM_001286810.2		c.20+488C>G		intron	N/A	NP_001273739.1	A0A0A0MQT4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCAF10	ENST00000377724.8	TSL:1 MANE Select	c.269C>G	p.Pro90Arg	missense	Exon 1 of 7	ENSP00000366953.3	Q5QP82-1
	DCAF10	ENST00000242323.8	TSL:1	c.20+488C>G		intron	N/A	ENSP00000242323.8	A0A0A0MQT4
	ENSG00000255872	ENST00000540557.1	TSL:5	n.*761-17072G>C		intron	N/A	ENSP00000457548.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 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: 0.00000939 AC: 13 AN: 1384860 Hom.: 0 Cov.: 32 AF XY: 0.0000102 AC XY: 7 AN XY: 683502

African (AFR) AF: 0.00 AC: 0 AN: 28940

American (AMR) AF: 0.00 AC: 0 AN: 35120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24522

East Asian (EAS) AF: 0.00 AC: 0 AN: 33882

South Asian (SAS) AF: 0.00 AC: 0 AN: 77982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4452

European-Non Finnish (NFE) AF: 0.0000121 AC: 13 AN: 1076302

Other (OTH) AF: 0.00 AC: 0 AN: 57406

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2094

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	0.067
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.29
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.089	B
Vest4		0.089
MutPred		0.35		Loss of glycosylation at P90 (P = 0.003)
MVP		0.068
MPC		1.9
ClinPred		0.38	T
GERP RS		2.8
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.45
Mutation Taster		=94/6	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: rs1017451713; hg19: chr9-37801132;