rs398122524

Variant names:

• chr1-100011413-C-T
• rs398122524
• NM_012243.3:c.514C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_012243.3(SLC35A3):​c.514C>T​(p.Gln172*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000421 in 1,423,568 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q172Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SLC35A3 NM_012243.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.00
• Publications: 2 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 18 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 1-100011413-C-T is Pathogenic according to our data. Variant chr1-100011413-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 89029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.514C>T	p.Gln172*	stop_gained	Exon 5 of 8	NP_036375.1	Q9Y2D2-1
	SLC35A3	NM_001271685.2		c.640C>T	p.Gln214*	stop_gained	Exon 5 of 8	NP_001258614.1	Q9Y2D2-2
	SLC35A3	NM_001438725.1		c.514C>T	p.Gln172*	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.514C>T	p.Gln172*	stop_gained	Exon 5 of 8	ENSP00000433849.1	Q9Y2D2-1
	ENSG00000283761	ENST00000639037.1	TSL:5	c.514C>T	p.Gln172*	stop_gained	Exon 5 of 17	ENSP00000492745.1	A0A1W2PSA9
	SLC35A3	ENST00000638336.1	TSL:1	c.514C>T	p.Gln172*	stop_gained	Exon 5 of 6	ENSP00000491145.1	Q9Y2D2-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000421 AC: 6 AN: 1423568 Hom.: 0 Cov.: 25 AF XY: 0.00000424 AC XY: 3 AN XY: 708130

African (AFR) AF: 0.00 AC: 0 AN: 32550

American (AMR) AF: 0.00 AC: 0 AN: 41792

Ashkenazi Jewish (ASJ) AF: 0.000119 AC: 3 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 38824

South Asian (SAS) AF: 0.00 AC: 0 AN: 79726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1088746

Other (OTH) AF: 0.00 AC: 0 AN: 58678

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autism spectrum disorder - epilepsy - arthrogryposis syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.0
Vest4		0.60
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs398122524; hg19: chr1-100476969;