Genetic Variant UBALD1:p.Pro131Ala (chr16-4609776-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145253.3(UBALD1):c.391C>G(p.Pro131Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000365 in 1,508,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P131L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

UBALD1
NM_145253.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29

Variant links:

Genes affected

UBALD1 (HGNC:29576): (UBA like domain containing 1)

UBALD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.103913516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBALD1	NM_145253.3 link	c.391C>G	p.Pro131Ala	missense_variant	Exon 3 of 3	ENST00000283474.12	NP_660296.1	Q8TB05-1
UBALD1	NM_001330467.2 link	c.316C>G	p.Pro106Ala	missense_variant	Exon 3 of 3		NP_001317396.1	Q8TB05K7EM88
UBALD1	NM_001411032.1 link	c.*207C>G		3_prime_UTR_variant	Exon 3 of 3		NP_001397961.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBALD1	ENST00000283474.12 link	c.391C>G	p.Pro131Ala	missense_variant	Exon 3 of 3	1	NM_145253.3	ENSP00000283474.6		Q8TB05-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000671

AC:

AN:

148974

AF XY:

0.0000123

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000143

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1356408

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

664826

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29632

American (AMR)

AF:

0.00

AC:

AN:

28186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19578

East Asian (EAS)

AF:

0.00

AC:

AN:

37756

South Asian (SAS)

AF:

0.00

AC:

AN:

70262

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4988

European-Non Finnish (NFE)

AF:

0.0000479

AC:

AN:

1064092

Other (OTH)

AF:

0.0000180

AC:

AN:

55600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152012

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67938

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000873

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.391C>G (p.P131A) alteration is located in exon 3 (coding exon 3) of the UBALD1 gene. This alteration results from a C to G substitution at nucleotide position 391, causing the proline (P) at amino acid position 131 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0054

.;.;T;T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.80

T;T;T;T;T

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.10

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;.;L;.;.

PhyloP100

2.3

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.9

.;.;N;.;.

REVEL

Benign

0.082

Sift

Benign

0.035

.;.;D;.;.

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.0010, 0.0

.;.;B;B;.

Vest4

0.18

MVP

0.15

MPC

0.16

ClinPred

0.15

GERP RS

3.1

Varity_R

0.069

gMVP

0.32

Mutation Taster

=86/14

polymorphism

(source)

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

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16-4609776-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over