1-99993594-G-A

Position:

• chr1-99993594-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012243.3(SLC35A3):​c.40G>A​(p.Val14Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SLC35A3 NM_012243.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.44

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]

LOC124904230 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41220826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC35A3	NM_012243.3	c.40G>A	p.Val14Ile	missense_variant	2/8	ENST00000533028.8	NP_036375.1
LOC124904230	XR_007066249.1	n.279+44136C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC35A3	ENST00000533028.8	c.40G>A	p.Val14Ile	missense_variant	2/8	1	NM_012243.3	ENSP00000433849	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151904 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461722 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151904 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74210

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autism spectrum disorder - epilepsy - arthrogryposis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2021

This sequence change replaces valine with isoleucine at codon 14 of the SLC35A3 protein (p.Val14Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SLC35A3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Arthrogryposis multiplex congenita Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;T;.;.;.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;L;.;L;.;.;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.46	.;.;N;.;.;.;.;N;.;.;.;.;.;N;.;.
REVEL	Benign	0.20
Sift	Benign	0.30	.;.;T;.;.;.;.;T;.;.;.;.;.;T;.;.
Sift4G	Benign	0.35	.;T;T;.;.;.;.;T;.;.;.;.;.;T;.;.
Polyphen		0.086	.;B;B;.;.;.;.;B;.;.;.;.;.;.;.;.
Vest4		0.42, 0.45, 0.41
MutPred		0.66		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.63
ClinPred		0.69	D
GERP RS		5.6
Varity_R		0.16
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs1392040093; hg19: chr1-100459150;