Genetic Variant SLC35A3:c.-19+415A>G (chr1-99970577-A-G) – 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_001271685.2(SLC35A3):c.41A>G(p.Asp14Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 1,535,706 control chromosomes in the GnomAD database, including 1,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 152 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1373 hom. )

Consequence

SLC35A3
NM_001271685.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.485

Publications

11 publications found

Variant links:

Genes affected

SLC35A3 (HGNC:11023): (solute carrier family 35 member A3) This gene encodes a UDP-N-acetylglucosamine transporter found in the golgi apparatus membrane. In cattle, a missense mutation in this gene causes complex vertebral malformation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

SLC35A3 Gene-Disease associations (from GenCC):

autism spectrum disorder - epilepsy - arthrogryposis syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

SLC35A3 links:

ENSG00000283761 (HGNC:):

ENSG00000283761 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 (MetaRNN=0.0020925999).

BP6

Variant 1-99970577-A-G is Benign according to our data. Variant chr1-99970577-A-G is described in ClinVar as Benign. ClinVar VariationId is 1185185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0432 (6569/152164) while in subpopulation AFR AF = 0.0505 (2097/41498). AF 95% confidence interval is 0.0487. There are 152 homozygotes in GnomAd4. There are 3086 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 152 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271685.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC35A3	NM_012243.3	MANE Select	c.-19+415A>G		intron	N/A	NP_036375.1	Q9Y2D2-1
SLC35A3	NM_001271685.2		c.41A>G	p.Asp14Gly	missense	Exon 1 of 8	NP_001258614.1	Q9Y2D2-2
SLC35A3	NM_001438725.1		c.-118+415A>G		intron	N/A	NP_001425654.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC35A3	ENST00000533028.8	TSL:1 MANE Select	c.-19+415A>G	intron	N/A	ENSP00000433849.1	Q9Y2D2-1
ENSG00000283761	ENST00000639037.1	TSL:5	c.-19+415A>G	intron	N/A	ENSP00000492745.1	A0A1W2PSA9
SLC35A3	ENST00000638336.1	TSL:1	c.-19+415A>G	intron	N/A	ENSP00000491145.1	Q9Y2D2-3

Frequencies

GnomAD3 genomes

AF:

0.0430

AC:

6542

AN:

152046

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0501

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.0385

Gnomad ASJ

AF:

0.0386

Gnomad EAS

AF:

0.0407

Gnomad SAS

AF:

0.0319

Gnomad FIN

AF:

0.0212

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0433

Gnomad OTH

AF:

0.0504

GnomAD2 exomes

AF:

0.0379

AC:

5192

AN:

136918

AF XY:

0.0378

show subpopulations

Gnomad AFR exome

AF:

0.0535

Gnomad AMR exome

AF:

0.0212

Gnomad ASJ exome

AF:

0.0387

Gnomad EAS exome

AF:

0.0383

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0452

Gnomad OTH exome

AF:

0.0424

GnomAD4 exome

AF:

0.0428

AC:

59221

AN:

1383542

Hom.:

1373

Cov.:

AF XY:

0.0424

AC XY:

28956

AN XY:

682716

show subpopulations

African (AFR)

AF:

0.0486

AC:

1536

AN:

31580

American (AMR)

AF:

0.0226

AC:

805

AN:

35694

Ashkenazi Jewish (ASJ)

AF:

0.0405

AC:

1020

AN:

25172

East Asian (EAS)

AF:

0.0231

AC:

826

AN:

35732

South Asian (SAS)

AF:

0.0359

AC:

2845

AN:

79224

European-Finnish (FIN)

AF:

0.0277

AC:

939

AN:

33886

Middle Eastern (MID)

AF:

0.0469

AC:

267

AN:

5696

European-Non Finnish (NFE)

AF:

0.0450

AC:

48493

AN:

1078670

Other (OTH)

AF:

0.0430

AC:

2490

AN:

57888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

2906

5812

8718

11624

14530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1814

3628

5442

7256

9070

<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:

0.0432

AC:

6569

AN:

152164

Hom.:

152

Cov.:

AF XY:

0.0415

AC XY:

3086

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0505

AC:

2097

AN:

41498

American (AMR)

AF:

0.0384

AC:

588

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0386

AC:

134

AN:

3468

East Asian (EAS)

AF:

0.0410

AC:

212

AN:

5166

South Asian (SAS)

AF:

0.0324

AC:

156

AN:

4820

European-Finnish (FIN)

AF:

0.0212

AC:

225

AN:

10606

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0433

AC:

2945

AN:

68002

Other (OTH)

AF:

0.0499

AC:

105

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

329

658

986

1315

1644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0412

Hom.:

209

Bravo

AF:

0.0449

TwinsUK

AF:

0.0494

AC:

183

ALSPAC

AF:

0.0457

AC:

176

ExAC

AF:

0.0327

AC:

584

Asia WGS

AF:

0.0570

AC:

198

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autism spectrum disorder - epilepsy - arthrogryposis syndrome (1)

SLC35A3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.9

(source)

DANN

Uncertain

0.99

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

PhyloP100

0.48

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.080

REVEL

Benign

0.026

Sift

Benign

0.34

Sift4G

Benign

0.068

Polyphen

0.0

Vest4

0.041

ClinPred

0.011

GERP RS

0.61

PromoterAI

-0.059

Neutral

(source)

gMVP

0.20

Mutation Taster

=100/0

polymorphism (auto)

(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