6-87477478-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006416.5(SLC35A1):c.133A>G(p.Thr45Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,614,086 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 9 hom. )

Consequence

SLC35A1
NM_006416.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.49

Variant links:

Genes affected

SLC35A1 (HGNC:11021): (solute carrier family 35 member A1) The protein encoded by this gene is found in the membrane of the Golgi apparatus, where it transports nucleotide sugars into the Golgi. One such nucleotide sugar is CMP-sialic acid, which is imported into the Golgi by the encoded protein and subsequently glycosylated. Defects in this gene are a cause of congenital disorder of glycosylation type 2F (CDG2F). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2009]

SLC35A1 links:

ENSG00000213204 (HGNC:):

ENSG00000213204 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014591694).

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35A1	NM_006416.5 link	c.133A>G	p.Thr45Ala	missense_variant	Exon 2 of 8	ENST00000369552.9	NP_006407.1	P78382-1
SLC35A1	NM_001168398.2 link	c.133A>G	p.Thr45Ala	missense_variant	Exon 2 of 7		NP_001161870.1	P78382-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC35A1	ENST00000369552.9 link	c.133A>G	p.Thr45Ala	missense_variant	Exon 2 of 8	1	NM_006416.5	ENSP00000358565.4	P78382-1
ENSG00000213204	ENST00000507897.5 link	n.*177A>G		non_coding_transcript_exon_variant	Exon 14 of 16	2		ENSP00000426769.1
ENSG00000213204	ENST00000507897.5 link	n.*177A>G		3_prime_UTR_variant	Exon 14 of 16	2		ENSP00000426769.1

Frequencies

GnomAD3 genomes

AF:

0.00251

AC:

382

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00406

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00274

AC:

689

AN:

251454

Hom.:

AF XY:

0.00266

AC XY:

361

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00170

Gnomad FIN exome

AF:

0.00416

Gnomad NFE exome

AF:

0.00418

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00357

AC:

5213

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

2567

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00184

Gnomad4 FIN exome

AF:

0.00485

Gnomad4 NFE exome

AF:

0.00405

Gnomad4 OTH exome

AF:

0.00325

GnomAD4 genome

AF:

0.00251

AC:

382

AN:

152294

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.00406

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00326

Hom.:

Bravo

AF:

0.00215

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00277

AC:

336

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00373

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Jun 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC35A1: BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

SLC35A1-congenital disorder of glycosylation

Pathogenic:1Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC35A1 p.Thr45Ala variant was not identified in the literature but was identified in dbSNP (ID: rs145006535), LOVD 3.0 and ClinVar (classified as uncertain significance by Illumina and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, and as likely benign by Invitae). The variant was identified in control databases in 785 of 282850 chromosomes (3 homozygous) at a frequency of 0.002775 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 542 of 129166 chromosomes (freq: 0.004196), Other in 30 of 7228 chromosomes (freq: 0.004151), European (Finnish) in 104 of 25124 chromosomes (freq: 0.004139), South Asian in 52 of 30612 chromosomes (freq: 0.001699), Latino in 37 of 35440 chromosomes (freq: 0.001044), Ashkenazi Jewish in 9 of 10370 chromosomes (freq: 0.000868) and African in 11 of 24960 chromosomes (freq: 0.000441), but was not observed in the East Asian population. The p.Thr45 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

SLC35A1-related disorder

Benign:1

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;T;D;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.8

M;.;M;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.8

D;D;D;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.0050

D;D;D;.

Sift4G

Uncertain

0.014

D;D;D;D

Polyphen

1.0

.;.;D;.

Vest4

0.74

MVP

0.67

MPC

0.34

ClinPred

0.038

GERP RS

5.6

Varity_R

0.49

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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