rs1135401959

Positions:

• chr21-33581315-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_017613.4(DONSON):​c.1337T>C​(p.Met446Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DONSON NM_017613.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.96

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 21-33581315-A-G is Pathogenic according to our data. Variant chr21-33581315-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 431415.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-33581315-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DONSON	NM_017613.4	c.1337T>C	p.Met446Thr	missense_variant	8/10	ENST00000303071.10	NP_060083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DONSON	ENST00000303071.10	c.1337T>C	p.Met446Thr	missense_variant	8/10	1	NM_017613.4	ENSP00000307143.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Microcephaly, short stature, and limb abnormalities Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.018	D
MutationAssessor	Uncertain	2.9	.;.;M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.92
MVP		0.61
MPC		0.47
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs1135401959; hg19: chr21-34953621;