rs118203946

Positions:

• chr1-11274060-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity UBIA1_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_013319.3
• 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 id is 41408.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 1-11274060-G-C is Pathogenic according to our data. Variant chr1-11274060-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 857.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-11274060-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2013

- -

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;.
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
Varity_R		0.89
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203946; hg19: chr1-11334117;