Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_StrongBP7BS1BS2

The NM_001272071.2(AP1S2):c.288T>C(p.Ser96Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,190,496 control chromosomes in the GnomAD database, including 50 homozygotes. There are 915 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 22 hom., 420 hem., cov: 23)

Exomes 𝑓: 0.0018 ( 28 hom. 495 hem. )

Consequence

AP1S2
NM_001272071.2 splice_region, synonymous

Scores

Splicing: ADA: 0.008992

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.467

Publications

1 publications found

Variant links:

Genes affected

AP1S2 (HGNC:560): (adaptor related protein complex 1 subunit sigma 2) Adaptor protein complex 1 is found at the cytoplasmic face of coated vesicles located at the Golgi complex, where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. This complex is a heterotetramer composed of two large, one medium, and one small adaptin subunit. The protein encoded by this gene serves as the small subunit of this complex and is a member of the adaptin protein family. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

AP1S2 Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability 5
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
fried syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
autism spectrum disorder
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

AP1S2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP6

Variant X-15845903-A-G is Benign according to our data. Variant chrX-15845903-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.467 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (1555/111965) while in subpopulation AFR AF = 0.0458 (1412/30827). AF 95% confidence interval is 0.0438. There are 22 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001272071.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AP1S2	NM_001272071.2	MANE Select	c.288T>C	p.Ser96Ser	splice_region synonymous	Exon 3 of 6	NP_001259000.1
AP1S2	NM_001369007.1		c.288T>C	p.Ser96Ser	splice_region synonymous	Exon 3 of 5	NP_001355936.1
AP1S2	NM_001440864.1		c.288T>C	p.Ser96Ser	splice_region synonymous	Exon 3 of 6	NP_001427793.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AP1S2	ENST00000672987.1	MANE Select	c.288T>C	p.Ser96Ser	splice_region synonymous	Exon 3 of 6	ENSP00000500695.1
AP1S2	ENST00000329235.6	TSL:1	c.288T>C	p.Ser96Ser	splice_region synonymous	Exon 3 of 5	ENSP00000328789.2
AP1S2	ENST00000545766.7	TSL:1	c.156T>C	p.Ser52Ser	splice_region synonymous	Exon 3 of 6	ENSP00000444957.3

Frequencies

GnomAD3 genomes

AF:

0.0139

AC:

1554

AN:

111916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00797

Gnomad ASJ

AF:

0.00834

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000367

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.000357

Gnomad OTH

AF:

0.0107

GnomAD2 exomes

AF:

0.00417

AC:

764

AN:

183227

AF XY:

0.00277

show subpopulations

Gnomad AFR exome

AF:

0.0466

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00177

AC:

1907

AN:

1078531

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

495

AN XY:

346333

show subpopulations

African (AFR)

AF:

0.0499

AC:

1298

AN:

26012

American (AMR)

AF:

0.00316

AC:

111

AN:

35178

Ashkenazi Jewish (ASJ)

AF:

0.00711

AC:

137

AN:

19260

East Asian (EAS)

AF:

0.00

AC:

AN:

30075

South Asian (SAS)

AF:

0.0000931

AC:

AN:

53678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40510

Middle Eastern (MID)

AF:

0.00319

AC:

AN:

4079

European-Non Finnish (NFE)

AF:

0.000245

AC:

202

AN:

824322

Other (OTH)

AF:

0.00310

AC:

141

AN:

45417

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0139

AC:

1555

AN:

111965

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

420

AN XY:

34159

show subpopulations

African (AFR)

AF:

0.0458

AC:

1412

AN:

30827

American (AMR)

AF:

0.00796

AC:

AN:

10549

Ashkenazi Jewish (ASJ)

AF:

0.00834

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3613

South Asian (SAS)

AF:

0.000368

AC:

AN:

2714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6058

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000357

AC:

AN:

53156

Other (OTH)

AF:

0.0106

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00507

Hom.:

209

Bravo

AF:

0.0163

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

0.47

Mutation Taster

=60/40

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0090

dbscSNV1_RF

Benign

0.32

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs61741688

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over