1-100011380-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012243.3(SLC35A3):​c.481C>A​(p.Gln161Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,374,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q161Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SLC35A3 NM_012243.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.080141336).

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>A	p.Gln161Lys	missense	Exon 5 of 8	NP_036375.1	Q9Y2D2-1
	SLC35A3	NM_001271685.2		c.607C>A	p.Gln203Lys	missense	Exon 5 of 8	NP_001258614.1	Q9Y2D2-2
	SLC35A3	NM_001438725.1		c.481C>A	p.Gln161Lys	missense	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>A	p.Gln161Lys	missense	Exon 5 of 8	ENSP00000433849.1	Q9Y2D2-1
	ENSG00000283761	ENST00000639037.1	TSL:5	c.481C>A	p.Gln161Lys	missense	Exon 5 of 17	ENSP00000492745.1	A0A1W2PSA9
	SLC35A3	ENST00000638336.1	TSL:1	c.481C>A	p.Gln161Lys	missense	Exon 5 of 6	ENSP00000491145.1	Q9Y2D2-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1374860 Hom.: 0 Cov.: 25 AF XY: 0.00000146 AC XY: 1 AN XY: 683646

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00 AC: 0 AN: 1063616

Other (OTH) AF: 0.0000177 AC: 1 AN: 56584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.56
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.018
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N
PhyloP100		2.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.088
Sift	Benign	1.0	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.36		Gain of ubiquitination at Q161 (P = 0.0051)
MVP		0.67
ClinPred		0.18	T
GERP RS		5.5
Varity_R		0.30
gMVP		0.10
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1553203137; hg19: chr1-100476936;