rs779803447

Variant names:

• chr21-33583576-G-C
• rs779803447
• NM_017613.4:c.876C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-33583576-G-C
• chr21-33583576-G-A
• chr21-33583576-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM2 PP3_Moderate PP5_Moderate

The NM_017613.4(DONSON):​c.876C>G​(p.Phe292Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005085918: Cells from a patient compound heterozygous for this variant showed defective intra-S phase checkpoint activation, elevated DNA damage and chromosome breakage, and reduced DONSON protein levels. HeLa cells transfected with this variant showed diffuse protein mislocalisation compared to wild type which was localised in the nucleus (PMID:28191891).".

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DONSON NM_017613.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.70
• Publications: 3 publications found

Genes affected

DONSON (HGNC:2993): (DNA replication fork stabilization factor DONSON) This gene lies downstream of the SON gene and spans 10 kb on chromosome 21. The function of this gene is unknown. [provided by RefSeq, Jul 2008]

DONSON Gene-Disease associations (from GenCC):

• microcephaly, short stature, and limb abnormalities

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005085918: Cells from a patient compound heterozygous for this variant showed defective intra-S phase checkpoint activation, elevated DNA damage and chromosome breakage, and reduced DONSON protein levels. HeLa cells transfected with this variant showed diffuse protein mislocalisation compared to wild type which was localised in the nucleus (PMID: 28191891).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 21-33583576-G-C is Pathogenic according to our data. Variant chr21-33583576-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 431420.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017613.4. 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
	DONSON	NM_017613.4	MANE Select	c.876C>G	p.Phe292Leu	missense	Exon 5 of 10	NP_060083.1	Q9NYP3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DONSON	ENST00000303071.10	TSL:1 MANE Select	c.876C>G	p.Phe292Leu	missense	Exon 5 of 10	ENSP00000307143.4	Q9NYP3-1
	DONSON	ENST00000442660.5	TSL:1	n.464+1014C>G		intron	N/A	ENSP00000408788.1	H7C304
	DONSON	ENST00000444517.5	TSL:1	n.464+1014C>G		intron	N/A	ENSP00000392405.1	H7C006

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251458 AF XY: 0.00000736

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: 0.00000137 AC: 2 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727144

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111844

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Microcephaly, short stature, and limb abnormalities (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.84		Loss of catalytic residue at F292 (P = 0.0207)
MVP		0.39
MPC		0.51
ClinPred		1.0	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.88
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs779803447; hg19: chr21-34955882;