9-37801065-C-A

Variant names:

• chr9-37801065-C-A
• rs753748989
• NM_024345.5:c.199C>A

Variant summary

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

The NM_024345.5(DCAF10):​c.199C>A​(p.Arg67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,379,894 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. 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. R67C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DCAF10 NM_024345.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• 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: 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=0.16841489).

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.199C>A	p.Arg67Ser	missense	Exon 1 of 7	NP_077321.3
	DCAF10	NM_001286810.2		c.20+418C>A		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.199C>A	p.Arg67Ser	missense	Exon 1 of 7	ENSP00000366953.3	Q5QP82-1
	DCAF10	ENST00000242323.8	TSL:1	c.20+418C>A		intron	N/A	ENSP00000242323.8	A0A0A0MQT4
	ENSG00000255872	ENST00000540557.1	TSL:5	n.*761-17002G>T		intron	N/A	ENSP00000457548.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379894 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 681874

African (AFR) AF: 0.00 AC: 0 AN: 28974

American (AMR) AF: 0.00 AC: 0 AN: 36590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24506

East Asian (EAS) AF: 0.00 AC: 0 AN: 33934

South Asian (SAS) AF: 0.00 AC: 0 AN: 78286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4046

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079376

Other (OTH) AF: 0.00 AC: 0 AN: 57434

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.86
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.12
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.036
Sift	Benign	0.059	T
Sift4G	Benign	0.33	T
Polyphen		0.049	B
Vest4		0.17
MutPred		0.37		Gain of phosphorylation at R67 (P = 0.0024)
MVP		0.19
MPC		1.4
ClinPred		0.15	T
GERP RS		-0.57
PromoterAI		0.072	Neutral
Varity_R		0.11
gMVP		0.28
Mutation Taster		=97/3	polymorphism

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

dbSNP: rs753748989; hg19: chr9-37801062;