chr6-87477478-A-G

Variant names:

• chr6-87477478-A-G
• rs145006535
• NM_006416.5:c.133A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:7
• Conservation: PhyloP100: 7.49
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• SLC35A1-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ENSG00000213204 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014591694).
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006416.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35A1	NM_006416.5	MANE Select	c.133A>G	p.Thr45Ala	missense	Exon 2 of 8	NP_006407.1	P78382-1
	SLC35A1	NM_001168398.2		c.133A>G	p.Thr45Ala	missense	Exon 2 of 7	NP_001161870.1	P78382-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35A1	ENST00000369552.9	TSL:1 MANE Select	c.133A>G	p.Thr45Ala	missense	Exon 2 of 8	ENSP00000358565.4	P78382-1
	SLC35A1	ENST00000369556.7	TSL:1	c.133A>G	p.Thr45Ala	missense	Exon 2 of 7	ENSP00000358569.3	P78382-2
	ENSG00000213204	ENST00000507897.5	TSL:2	n.*177A>G		non_coding_transcript_exon	Exon 14 of 16	ENSP00000426769.1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152176 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00274 AC: 689 AN: 251454 AF XY: 0.00266

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 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.: 9 Cov.: 31 AF XY: 0.00353 AC XY: 2567 AN XY: 727204

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.000984 AC: 44 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00184 AC: 159 AN: 86256

European-Finnish (FIN) AF: 0.00485 AC: 259 AN: 53414

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00405 AC: 4499 AN: 1111944

Other (OTH) AF: 0.00325 AC: 196 AN: 60394

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74472

African (AFR) AF: 0.000602 AC: 25 AN: 41556

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00406 AC: 276 AN: 68016

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00330 Hom.: 5

Bravo AF: 0.00215

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00277 AC: 336

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00373

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
1	-	1	SLC35A1-congenital disorder of glycosylation (2)
-	-	1	not specified (1)
-	-	1	SLC35A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.67
MPC		0.34
ClinPred		0.038	T
GERP RS		5.6
Varity_R		0.49
gMVP		0.41
Mutation Taster		=189/111	polymorphism

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

Other links and lift over

dbSNP: rs145006535; hg19: chr6-88187196;