1-67009089-T-A

Variant names:

• chr1-67009089-T-A
• rs199878087
• NM_015139.3:c.955A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015139.3(SLC35D1):​c.955A>T​(p.Ile319Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000771 in 1,296,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I319V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: SLC35D1 NM_015139.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.23
• Publications: 0 publications found

Genes affected

SLC35D1 (HGNC:20800): (solute carrier family 35 member D1) Glycosylation of cellular glycoconjugates occurs in the endoplasmic reticulum (ER) and Golgi compartment, and requires transport of nucleotide sugars from the cytosol into the lumen of the ER and Golgi by specific transporters. The protein encoded by this gene resides in the ER, and transports both UDP-glucuronic acid (UDP-GlcA) and UDP-N-acetylgalactosamine (UDP-GalNAc) from the cytoplasm to the ER lumen. It may participate in glucuronidation and/or chondroitin sulfate biosynthesis. Mutations in this gene are associated with Schneckenbecken dysplasia.[provided by RefSeq, Sep 2009]

SLC35D1 Gene-Disease associations (from GenCC):

• schneckenbecken dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015139.3. 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
	SLC35D1	NM_015139.3	MANE Select	c.955A>T	p.Ile319Phe	missense	Exon 11 of 12	NP_055954.1	Q9NTN3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35D1	ENST00000235345.6	TSL:1 MANE Select	c.955A>T	p.Ile319Phe	missense	Exon 11 of 12	ENSP00000235345.5	Q9NTN3-1
	SLC35D1	ENST00000901512.1		c.1036A>T	p.Ile346Phe	missense	Exon 12 of 13	ENSP00000571571.1
	SLC35D1	ENST00000901514.1		c.952A>T	p.Ile318Phe	missense	Exon 11 of 12	ENSP00000571573.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.71e-7 AC: 1 AN: 1296878 Hom.: 0 Cov.: 19 AF XY: 0.00000153 AC XY: 1 AN XY: 653088

⚠️ 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: 30162

American (AMR) AF: 0.00 AC: 0 AN: 44114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24660

East Asian (EAS) AF: 0.00 AC: 0 AN: 38500

South Asian (SAS) AF: 0.00 AC: 0 AN: 81972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 965200

Other (OTH) AF: 0.00 AC: 0 AN: 54406

⚠️ 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	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.079	T
Polyphen		0.99	D
Vest4		0.96
MutPred		0.45		Loss of glycosylation at S320 (P = 0.1763)
MVP		0.91
MPC		0.95
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.85
gMVP		0.89
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs199878087; hg19: chr1-67474772;