Genetic Variant NM_138927.4:c.78-20C>T (chr21-33546193-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_138927.4(SON):c.78-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,576,156 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 25 hom., cov: 33)

Exomes 𝑓: 0.022 ( 362 hom. )

Consequence

SON
NM_138927.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.08

Publications

2 publications found

Variant links:

Genes affected

SON (HGNC:11183): (SON DNA and RNA binding protein) This gene encodes a protein that contains multiple simple repeats. The encoded protein binds RNA and promotes pre-mRNA splicing, particularly of transcripts with poor splice sites. The protein also recognizes a specific DNA sequence found in the human hepatitis B virus (HBV) and represses HBV core promoter activity. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

SON Gene-Disease associations (from GenCC):

ZTTK syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Illumina, PanelApp Australia

SON links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 21-33546193-C-T is Benign according to our data. Variant chr21-33546193-C-T is described in ClinVar as Benign. ClinVar VariationId is 1603796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0155 (2362/152068) while in subpopulation NFE AF = 0.0232 (1575/67988). AF 95% confidence interval is 0.0222. There are 25 homozygotes in GnomAd4. There are 1124 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2362 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138927.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SON	NM_138927.4	MANE Select	c.78-20C>T	intron	N/A	NP_620305.3	P18583-1
SON	NM_032195.3		c.78-20C>T	intron	N/A	NP_115571.3	P18583-3
SON	NM_001291411.2		c.78-20C>T	intron	N/A	NP_001278340.2	P18583-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SON	ENST00000356577.10	TSL:1 MANE Select	c.78-20C>T	intron	N/A	ENSP00000348984.4	P18583-1
SON	ENST00000300278.8	TSL:1	c.78-20C>T	intron	N/A	ENSP00000300278.2	P18583-3
SON	ENST00000381692.6	TSL:1	c.78-20C>T	intron	N/A	ENSP00000371111.2	J3QSZ5

Frequencies

GnomAD3 genomes

AF:

0.0155

AC:

2360

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00438

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0154

GnomAD2 exomes

AF:

0.0170

AC:

3831

AN:

225556

AF XY:

0.0172

show subpopulations

Gnomad AFR exome

AF:

0.00444

Gnomad AMR exome

AF:

0.00731

Gnomad ASJ exome

AF:

0.0182

Gnomad EAS exome

AF:

0.0000603

Gnomad FIN exome

AF:

0.0278

Gnomad NFE exome

AF:

0.0236

Gnomad OTH exome

AF:

0.0215

GnomAD4 exome

AF:

0.0216

AC:

30732

AN:

1424088

Hom.:

362

Cov.:

AF XY:

0.0213

AC XY:

15056

AN XY:

707646

show subpopulations

African (AFR)

AF:

0.00258

AC:

AN:

31354

American (AMR)

AF:

0.00797

AC:

282

AN:

35388

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

448

AN:

24650

East Asian (EAS)

AF:

0.0000510

AC:

AN:

39250

South Asian (SAS)

AF:

0.00717

AC:

577

AN:

80426

European-Finnish (FIN)

AF:

0.0281

AC:

1486

AN:

52890

Middle Eastern (MID)

AF:

0.00481

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.0243

AC:

26666

AN:

1095710

Other (OTH)

AF:

0.0198

AC:

1163

AN:

58806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1209

2418

3626

4835

6044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1022

2044

3066

4088

5110

<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:

0.0155

AC:

2362

AN:

152068

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

1124

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00436

AC:

181

AN:

41478

American (AMR)

AF:

0.0155

AC:

236

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00601

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0227

AC:

240

AN:

10554

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0232

AC:

1575

AN:

67988

Other (OTH)

AF:

0.0152

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

124

248

372

496

620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0193

Hom.:

Bravo

AF:

0.0150

Asia WGS

AF:

0.00347

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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