chr1-67053821-T-G

Variant names:

• chr1-67053821-T-G
• rs267607062
• NM_015139.3:c.193A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_015139.3(SLC35D1):​c.193A>C​(p.Thr65Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,036 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC35D1 NM_015139.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.77
• Publications: 6 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 1-67053821-T-G is Pathogenic according to our data. Variant chr1-67053821-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1129.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35D1	NM_015139.3	MANE Select	c.193A>C	p.Thr65Pro	missense	Exon 1 of 12	NP_055954.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35D1	ENST00000235345.6	TSL:1 MANE Select	c.193A>C	p.Thr65Pro	missense	Exon 1 of 12	ENSP00000235345.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458036 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725354

⚠️ 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: 33126

American (AMR) AF: 0.00 AC: 0 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39380

South Asian (SAS) AF: 0.00 AC: 0 AN: 85666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110272

Other (OTH) AF: 0.00 AC: 0 AN: 60176

⚠️ 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.: 33

Alfa AF: 0.0000688 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Schneckenbecken dysplasia Pathogenic:1

Aug 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.85		Loss of methylation at R68 (P = 0.1062)
MVP		0.95
MPC		0.82
ClinPred		1.0	D
GERP RS		3.3
PromoterAI		0.039	Neutral
Varity_R		0.98
gMVP		0.73
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs267607062; hg19: chr1-67519504;