1-99993575-C-G

Position:

• chr1-99993575-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_012243.3(SLC35A3):​c.21C>G​(p.Tyr7*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,642 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y7Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SLC35A3 NM_012243.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.11

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]

ENSG00000283761 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-99993575-C-G is Pathogenic according to our data. Variant chr1-99993575-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1433891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC35A3	NM_012243.3	c.21C>G	p.Tyr7*	stop_gained	2/8	ENST00000533028.8	NP_036375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC35A3	ENST00000533028.8	c.21C>G	p.Tyr7*	stop_gained	2/8	1	NM_012243.3	ENSP00000433849.1
ENSG00000283761	ENST00000639037.1	c.21C>G	p.Tyr7*	stop_gained	2/17	5		ENSP00000492745.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251276 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

The c.21C>G (p.Y7*) alteration, located in exon 2 (coding exon 1) of the SLC35A3 gene, consists of a C to G substitution at nucleotide position 21. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 7. The predicted stop codon occurs in the 5' end of the SLC35A3 gene. Premature termination codons in the 5&rsquo; end of a gene have been reported to escape nonsense-mediated mRNA decay and/or lead to re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). Direct evidence for this alteration is unavailable; however, premature termination codons are typically deleterious in nature. Based on data from gnomAD, the G allele has an overall frequency of <0.01% (5/251276) total alleles studied. The highest observed frequency was 0.01% (5/34564) of Latino alleles. Based on the available evidence, this alteration is classified as likely pathogenic. -

Autism spectrum disorder - epilepsy - arthrogryposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1433891). This variant has not been reported in the literature in individuals affected with SLC35A3-related conditions. This variant is present in population databases (rs775151826, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Tyr7*) in the SLC35A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC35A3 are known to be pathogenic (PMID: 24031089, 28328131). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.78	D
Vest4		0.45, 0.46, 0.52
GERP RS		2.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs775151826; hg19: chr1-100459131;