1-11273755-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013319.3(UBIAD1):c.224C>T(p.Ser75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,146 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (5 hom., cov: 31)
  • Exomes 𝑓: 0.011 (112 hom.)
• Consequence: UBIAD1 NM_013319.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.79

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006565273).
• BP6: Variant 1-11273755-C-T is Benign according to our data. Variant chr1-11273755-C-T is described in ClinVar as [Benign]. Clinvar id is 291821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11273755-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00796 (1212/152312) while in subpopulation NFE AF= 0.0125 (847/68024). AF 95% confidence interval is 0.0118. There are 5 homozygotes in gnomad4. There are 559 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBIAD1	NM_013319.3	c.224C>T	p.Ser75Phe	missense_variant	1/2	ENST00000376810.6
UBIAD1	NM_001330349.2	c.224C>T	p.Ser75Phe	missense_variant	1/3
UBIAD1	NM_001330350.2	c.224C>T	p.Ser75Phe	missense_variant	1/2
UBIAD1	XM_047418727.1	c.224C>T	p.Ser75Phe	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBIAD1	ENST00000376810.6	c.224C>T	p.Ser75Phe	missense_variant	1/2	1	NM_013319.3	P1
UBIAD1	ENST00000376804.2	c.224C>T	p.Ser75Phe	missense_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1214 AN: 152194 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00708 AC: 1780 AN: 251290 Hom.: 8 AF XY: 0.00711 AC XY: 966 AN XY: 135858

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.0106 AC: 15503 AN: 1461834 Hom.: 112 Cov.: 31 AF XY: 0.0103 AC XY: 7495 AN XY: 727218

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00771

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.00204

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00796 AC: 1212 AN: 152312 Hom.: 5 Cov.: 31 AF XY: 0.00750 AC XY: 559 AN XY: 74484

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0109 Hom.: 7

Bravo AF: 0.00849

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0122 AC: 105

ExAC AF: 0.00682 AC: 828

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0128

EpiControl AF: 0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	UBIAD1: BS1, BS2 -

Schnyder crystalline corneal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0066	T;T
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.27
Sift	Benign	0.30	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.064	B;.
Vest4		0.18
MVP		0.42
MPC		0.57
ClinPred		0.019	T
GERP RS		5.0
Varity_R		0.22
gMVP		0.31

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: rs114000606; hg19: chr1-11333812; COSMIC: COSV99060813; COSMIC: COSV99060813;