Genetic Variant NM_018389.5:c.503_505delTCT (chr11-45806301-CCTT-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3PM4_SupportingPP5

The NM_018389.5(SLC35C1):c.503_505delTCT(p.Phe168del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000675 in 1,612,702 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000946765: Experimental studies have shown that this variant affects SLC35C1 function (PMID:24403049).".

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 1 hom. )

Consequence

SLC35C1
NM_018389.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:2

Conservation

PhyloP100: 5.03

Publications

4 publications found

Variant links:

Genes affected

SLC35C1 (HGNC:20197): (solute carrier family 35 member C1) This gene encodes a GDP-fucose transporter that is found in the Golgi apparatus. Mutations in this gene result in congenital disorder of glycosylation type IIc. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

SLC35C1 Gene-Disease associations (from GenCC):

leukocyte adhesion deficiency type II
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, PanelApp Australia

SLC35C1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000946765: Experimental studies have shown that this variant affects SLC35C1 function (PMID: 24403049).

PM4

Nonframeshift variant in NON repetitive region in NM_018389.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 11-45806301-CCTT-C is Pathogenic according to our data. Variant chr11-45806301-CCTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 144046.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018389.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC35C1	NM_018389.5	MANE Select	c.503_505delTCT	p.Phe168del	disruptive_inframe_deletion	Exon 1 of 2	NP_060859.4
SLC35C1	NM_001425155.1		c.503_505delTCT	p.Phe168del	disruptive_inframe_deletion	Exon 2 of 3	NP_001412084.1	B3KQH0
SLC35C1	NM_001145265.2		c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	Exon 2 of 3	NP_001138737.1	Q96A29-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC35C1	ENST00000314134.4	TSL:1 MANE Select	c.503_505delTCT	p.Phe168del	disruptive_inframe_deletion	Exon 1 of 2	ENSP00000313318.3	Q96A29-1
SLC35C1	ENST00000442528.2	TSL:1	c.464_466delTCT	p.Phe155del	disruptive_inframe_deletion	Exon 2 of 3	ENSP00000412408.2	Q96A29-2
SLC35C1	ENST00000953729.1		c.503_505delTCT	p.Phe168del	disruptive_inframe_deletion	Exon 2 of 3	ENSP00000623788.1

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000320

AC:

AN:

250286

AF XY:

0.000340

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000191

Gnomad NFE exome

AF:

0.000644

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000698

AC:

1020

AN:

1460470

Hom.:

AF XY:

0.000679

AC XY:

493

AN XY:

726584

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000192

AC:

AN:

52030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000893

AC:

993

AN:

1112002

Other (OTH)

AF:

0.000199

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000453

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000970

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000608

Hom.:

Bravo

AF:

0.000423

EpiCase

AF:

0.000763

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leukocyte adhesion deficiency type II (7)

not provided (4)

SLC35C1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.0

Mutation Taster

=56/44

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