9-96324168-A-G

Position:

• chr9-96324168-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007001.3(SLC35D2):​c.754T>C​(p.Phe252Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000938 in 1,613,552 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (1 hom.)
• Consequence: SLC35D2 NM_007001.3 missense, splice_region
• Scores: Splicing: ADA: 0.01065
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.19

Genes affected

SLC35D2 (HGNC:20799): (solute carrier family 35 member D2) Nucleotide sugars, which are synthesized in the cytosol or the nucleus, are high-energy donor substrates for glycosyltransferases located in the lumen of the endoplasmic reticulum and Golgi apparatus. Translocation of nucleotide sugars from the cytosol into the lumen compartment is mediated by specific nucleotide sugar transporters, such as SLC35D2 (Suda et al., 2004 [PubMed 15082721]).[supplied by OMIM, Mar 2008]

ENSG00000285269 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19190684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC35D2	NM_007001.3	c.754T>C	p.Phe252Leu	missense_variant, splice_region_variant	10/12	ENST00000253270.13	NP_008932.2
SLC35D2	NM_001286990.2	c.490T>C	p.Phe164Leu	missense_variant, splice_region_variant	7/9		NP_001273919.1
SLC35D2	NR_104627.2	n.831T>C		splice_region_variant, non_coding_transcript_exon_variant	10/13
SLC35D2-HSD17B3	NR_182427.1	n.831T>C		splice_region_variant, non_coding_transcript_exon_variant	10/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC35D2	ENST00000253270.13	c.754T>C	p.Phe252Leu	missense_variant, splice_region_variant	10/12	1	NM_007001.3	ENSP00000253270.7
ENSG00000285269	ENST00000643789.1	n.355T>C		splice_region_variant, non_coding_transcript_exon_variant	6/22			ENSP00000494818.1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000498 AC: 125 AN: 251246 Hom.: 0 AF XY: 0.000471 AC XY: 64 AN XY: 135776

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000981 AC: 1434 AN: 1461292 Hom.: 1 Cov.: 30 AF XY: 0.000941 AC XY: 684 AN XY: 726942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74458

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000729 Hom.: 0

Bravo AF: 0.000544

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000764

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2024

The c.754T>C (p.F252L) alteration is located in exon 10 (coding exon 10) of the SLC35D2 gene. This alteration results from a T to C substitution at nucleotide position 754, causing the phenylalanine (F) at amino acid position 252 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.64	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.55
Sift	Benign	0.077	T;D
Sift4G	Benign	0.12	T;T
Polyphen		0.16	B;D
Vest4		0.78
MutPred		0.58		Gain of glycosylation at S257 (P = 0.4072);.;
MVP		0.55
MPC		0.33
ClinPred		0.24	T
GERP RS		4.2
Varity_R		0.60
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.092
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs78220385; hg19: chr9-99086450;