NM_017613.4:c.1466A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PS3BP4_StrongBS1BS2

The NM_017613.4(DONSON):c.1466A>C(p.Lys489Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000928 in 1,614,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002766865: "Western blot and immunoblot studies have shown this variant causes reduced DONSON protein levels (PMID:28191891)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K489I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 2 hom. )

Consequence

DONSON
NM_017613.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1B:4

Conservation

PhyloP100: -2.70

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

microcephaly, short stature, and limb abnormalities
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

DONSON links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002766865: "Western blot and immunoblot studies have shown this variant causes reduced DONSON protein levels (PMID: 28191891)."; SCV000742268: Functional analysis demonstrated the p.K489T alteration reduced protein levels and was unable to complement the loss of endogenous DONSON during replication fork stalling (Reynolds, 2017).

BP4

Computational evidence support a benign effect (MetaRNN=0.008210868).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000919 (140/152320) while in subpopulation AMR AF = 0.00176 (27/15302). AF 95% confidence interval is 0.00124. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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.1466A>C	p.Lys489Thr	missense	Exon 9 of 10	NP_060083.1	Q9NYP3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DONSON	ENST00000303071.10	TSL:1 MANE Select	c.1466A>C	p.Lys489Thr	missense	Exon 9 of 10	ENSP00000307143.4	Q9NYP3-1
DONSON	ENST00000442660.5	TSL:1	n.*495A>C		non_coding_transcript_exon	Exon 7 of 8	ENSP00000408788.1	H7C304
DONSON	ENST00000444517.5	TSL:1	n.*103A>C		non_coding_transcript_exon	Exon 4 of 5	ENSP00000392405.1	H7C006

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

141

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000974

AC:

245

AN:

251470

AF XY:

0.00104

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00724

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000888

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000929

AC:

1358

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000985

AC XY:

716

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.00107

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00685

AC:

179

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39692

South Asian (SAS)

AF:

0.000568

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000841

AC:

935

AN:

1111996

Other (OTH)

AF:

0.00166

AC:

100

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

151

226

302

377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000919

AC:

140

AN:

152320

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41574

American (AMR)

AF:

0.00176

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000361

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000988

AC:

120

EpiCase

AF:

0.000927

EpiControl

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly, short stature, and limb abnormalities (3)

not provided (2)

DONSON-related disorder (1)

Inborn genetic diseases (1)

Microcephaly (1)

Microcephaly-micromelia syndrome (1)

Microcephaly-micromelia syndrome;C4539873:Microcephaly, short stature, and limb abnormalities (1)

not specified (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.036

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.017

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.60

M_CAP

Benign

0.0070

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

PhyloP100

-2.7

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.4

REVEL

Benign

0.11

Sift

Benign

0.073

Sift4G

Benign

0.10

Polyphen

0.55

Vest4

0.20

MVP

0.16

MPC

0.18

ClinPred

0.030

GERP RS

-9.3

Varity_R

0.047

gMVP

0.49

Mutation Taster

=88/12

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over