1-100007096-A-T

Variant names:

• chr1-100007096-A-T
• rs754559092
• NM_012243.3:c.405A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012243.3(SLC35A3):​c.405A>T​(p.Lys135Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC35A3 NM_012243.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.946
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3375278).

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.405A>T	p.Lys135Asn	missense	Exon 4 of 8	NP_036375.1	Q9Y2D2-1
	SLC35A3	NM_001271685.2		c.531A>T	p.Lys177Asn	missense	Exon 4 of 8	NP_001258614.1	Q9Y2D2-2
	SLC35A3	NM_001438725.1		c.405A>T	p.Lys135Asn	missense	Exon 5 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.405A>T	p.Lys135Asn	missense	Exon 4 of 8	ENSP00000433849.1	Q9Y2D2-1
	ENSG00000283761	ENST00000639037.1	TSL:5	c.405A>T	p.Lys135Asn	missense	Exon 4 of 17	ENSP00000492745.1	A0A1W2PSA9
	SLC35A3	ENST00000638336.1	TSL:1	c.405A>T	p.Lys135Asn	missense	Exon 4 of 6	ENSP00000491145.1	Q9Y2D2-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.95
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.21
Sift	Benign	0.084	T
Sift4G	Benign	0.16	T
Polyphen		0.033	B
Vest4		0.42
MutPred		0.56		Loss of methylation at K135 (P = 0.0289)
MVP		0.70
ClinPred		0.75	D
GERP RS		0.60
Varity_R		0.28
gMVP		0.30
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs754559092; hg19: chr1-100472652;