Variant rs779149681 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_017613.4(DONSON):c.1047-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

DONSON
NM_017613.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.6194

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.388

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-33582064-T-C is Pathogenic according to our data. Variant chr21-33582064-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 431414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-33582064-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DONSON	NM_017613.4 linkuse as main transcript	c.1047-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000303071.10	NP_060083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DONSON	ENST00000303071.10 linkuse as main transcript	c.1047-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_017613.4	ENSP00000307143	P1	Q9NYP3-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251390

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461636

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly, short stature, and limb abnormalities

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2022	Variant summary: DONSON c.1047-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, multiple publications report the variant to have an impact on splicing, specifically a reduction in DONSON transcript levels compared to normal controls as well as significantly increased retention of intron 6 (Reynolds_2017, Evrony_2017). The variant allele was found at a frequency of 4.8e-05 in 251390 control chromosomes. c.1047-9A>G has been reported in the literature in multiple individuals affected with Microcephaly, Short Stature, And Limb Abnormalities including several members of the same family in the homozygous state (Reynolds_2017, Evrony_2017). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 20, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 05, 2017	- -

Microcephaly-micromelia syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 05, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 12, 2022	This sequence change falls in intron 6 of the DONSON gene. It does not directly change the encoded amino acid sequence of the DONSON protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs779149681, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in retention of intron 6 and introduces a premature termination codon (PMID: 28630177). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that this variant alters DONSON gene expression (PMID: 28191891). ClinVar contains an entry for this variant (Variation ID: 431414). This variant has been observed in individuals with DONSON-related conditions (PMID: 28191891, 28630177). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	Published functional studies demonstrate a damaging effect (Evrony et al., 2017; Reynolds et al., 2017); This variant is associated with the following publications: (PMID: 34426522, 29760432, 28191891, 31191207, 32552793, 28630177, 34645488) -

DONSON-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The DONSON c.1047-9A>G variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous and homozygous states in patients with microcephalic dwarfism or microcephaly micromelia syndrome, and segregates with the disease in affected family members (Reynolds et al. 2017. PubMed ID: 28191891; Evrony et al. 2017. PubMed ID: 28630177; Family 15DG2154 in Table S1, Maddirevula. 2020. PubMed ID: 32552793; Shamseldin et al. 2021. PubMed ID: 34645488). This variant is predicted to alter splicing based on available splicing prediction programs (Alamut Visual v2.11). In addition, RNA studies suggest that this variant causes intron 6 retention (Evrony et al. 2017. PubMed ID: 28630177). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.62

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.51

Position offset: -9

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over