rs118203946

Variant names:

• chr1-11274060-G-C
• rs118203946
• NM_013319.3:c.529G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_013319.3(UBIAD1):​c.529G>C​(p.Gly177Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G177E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBIAD1 NM_013319.3 missense, splice_region
• Scores: Splicing: ADA: 0.9979
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32
• Publications: 17 publications found

Genes affected

UBIAD1 (HGNC:30791): (UbiA prenyltransferase domain containing 1) This gene encodes a protein thought to be involved in cholesterol and phospholipid metabolism. Mutations in this gene are associated with Schnyder crystalline corneal dystrophy. [provided by RefSeq, Oct 2008]

UBIAD1 Gene-Disease associations (from GenCC):

• Schnyder corneal dystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11285644-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 41408.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-11274060-G-C is Pathogenic according to our data. Variant chr1-11274060-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 857.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBIAD1	NM_013319.3	c.529G>C	p.Gly177Arg	missense_variant, splice_region_variant	Exon 1 of 2	ENST00000376810.6	NP_037451.1
UBIAD1	NM_001330349.2	c.529G>C	p.Gly177Arg	missense_variant, splice_region_variant	Exon 1 of 3		NP_001317278.1
UBIAD1	NM_001330350.2	c.529G>C	p.Val177Leu	missense_variant, splice_region_variant	Exon 1 of 2		NP_001317279.1
UBIAD1	XM_047418727.1	c.529G>C	p.Gly177Arg	missense_variant, splice_region_variant	Exon 1 of 3		XP_047274683.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBIAD1	ENST00000376810.6	c.529G>C	p.Gly177Arg	missense_variant, splice_region_variant	Exon 1 of 2	1	NM_013319.3	ENSP00000366006.5
UBIAD1	ENST00000376804.2	c.529G>C	p.Val177Leu	missense_variant, splice_region_variant	Exon 1 of 2	2		ENSP00000366000.1
UBIAD1	ENST00000483738.1	c.127G>C	p.Gly43Arg	missense_variant, splice_region_variant	Exon 1 of 3	3		ENSP00000473453.1
UBIAD1	ENST00000486588.6	n.172G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000473612.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Schnyder crystalline corneal dystrophy Pathogenic:1

Feb 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	35
DANN	Benign	0.90
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.4	M;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.95	P;.
Vest4		0.78
MutPred		0.70		Gain of methylation at G177 (P = 0.0186);.;
MVP		0.97
MPC		1.3
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		-0.19	Neutral
Varity_R		0.89
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.060		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: rs118203946; hg19: chr1-11334117;