rs1553203137

Variant names:

• chr1-100011380-C-T
• rs1553203137
• NM_012243.3:c.481C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-100011380-C-T
• chr1-100011380-C-A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_012243.3(SLC35A3):​c.481C>T​(p.Gln161*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,374,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q161Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SLC35A3 NM_012243.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.97
• Publications: 0 publications found

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]

SLC35A3 Gene-Disease associations (from GenCC):

• autism spectrum disorder - epilepsy - arthrogryposis syndrome

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

ENSG00000283761 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-100011380-C-T is Pathogenic according to our data. Variant chr1-100011380-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541609.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012243.3. 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
	SLC35A3	NM_012243.3	MANE Select	c.481C>T	p.Gln161*	stop_gained	Exon 5 of 8	NP_036375.1	Q9Y2D2-1
	SLC35A3	NM_001271685.2		c.607C>T	p.Gln203*	stop_gained	Exon 5 of 8	NP_001258614.1	Q9Y2D2-2
	SLC35A3	NM_001438725.1		c.481C>T	p.Gln161*	stop_gained	Exon 6 of 9	NP_001425654.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35A3	ENST00000533028.8	TSL:1 MANE Select	c.481C>T	p.Gln161*	stop_gained	Exon 5 of 8	ENSP00000433849.1	Q9Y2D2-1
	ENSG00000283761	ENST00000639037.1	TSL:5	c.481C>T	p.Gln161*	stop_gained	Exon 5 of 17	ENSP00000492745.1	A0A1W2PSA9
	SLC35A3	ENST00000638336.1	TSL:1	c.481C>T	p.Gln161*	stop_gained	Exon 5 of 6	ENSP00000491145.1	Q9Y2D2-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1374860 Hom.: 0 Cov.: 25 AF XY: 0.00000293 AC XY: 2 AN XY: 683646

African (AFR) AF: 0.00 AC: 0 AN: 30478

American (AMR) AF: 0.00 AC: 0 AN: 33768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23630

East Asian (EAS) AF: 0.00 AC: 0 AN: 37974

South Asian (SAS) AF: 0.00 AC: 0 AN: 72038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1063616

Other (OTH) AF: 0.00 AC: 0 AN: 56584

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Autism spectrum disorder - epilepsy - arthrogryposis syndrome (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		2.0
Vest4		0.42
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=26/174	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553203137; hg19: chr1-100476936;