rs137902416

Positions:

• chr1-100015415-C-T

Variant summary

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

The NM_012243.3(SLC35A3):​c.748C>T​(p.Leu250Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,601,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SLC35A3 NM_012243.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.88

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]

LOC124904230 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC35A3	NM_012243.3	c.748C>T	p.Leu250Phe	missense_variant	6/8	ENST00000533028.8	NP_036375.1
LOC124904230	XR_007066249.1	n.279+22315G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC35A3	ENST00000533028.8	c.748C>T	p.Leu250Phe	missense_variant	6/8	1	NM_012243.3	ENSP00000433849	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151950 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000170 AC: 4 AN: 235512 Hom.: 0 AF XY: 0.0000236 AC XY: 3 AN XY: 127256

Gnomad AFR exome AF: 0.0000633

Gnomad AMR exome AF: 0.0000332

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: 0.00000915

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1449076 Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 11 AN XY: 720426

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.0000481

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000993

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151950 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74224

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000581 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autism spectrum disorder - epilepsy - arthrogryposis syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 250 of the SLC35A3 protein (p.Leu250Phe). This variant is present in population databases (rs137902416, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SLC35A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 541610). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC35A3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T;T;.;.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;.;.;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.3	.;M;M;.;.;.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.2	.;.;D;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Benign	0.25
Sift	Benign	0.079	.;.;T;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Uncertain	0.049	.;D;D;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.93	.;P;P;.;.;.;P;.;.;.;.;.;.;.;.
Vest4		0.71, 0.72
MVP		0.82
ClinPred		0.90	D
GERP RS		4.3
Varity_R		0.53
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs137902416; hg19: chr1-100480971;