Genetic Variant NM_145253.3:c.227C>T (chr16-4609940-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_145253.3(UBALD1):c.227C>T(p.Pro76Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,240 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

UBALD1
NM_145253.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.03

Publications

0 publications found

Variant links:

Genes affected

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

UBALD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBALD1	NM_145253.3 link	c.227C>T	p.Pro76Leu	missense_variant	Exon 3 of 3	ENST00000283474.12	NP_660296.1	Q8TB05-1
UBALD1	NM_001411032.1 link	c.*43C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001397961.1
UBALD1	NM_001330467.2 link	c.184-32C>T		intron_variant	Intron 2 of 2		NP_001317396.1	Q8TB05K7EM88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBALD1	ENST00000283474.12 link	c.227C>T	p.Pro76Leu	missense_variant	Exon 3 of 3	1	NM_145253.3	ENSP00000283474.6		Q8TB05-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33228

American (AMR)

AF:

0.00

AC:

AN:

43166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25418

East Asian (EAS)

AF:

0.00

AC:

AN:

39512

South Asian (SAS)

AF:

0.00

AC:

AN:

84628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104476

Other (OTH)

AF:

0.00

AC:

AN:

59696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.227C>T (p.P76L) alteration is located in exon 3 (coding exon 3) of the UBALD1 gene. This alteration results from a C to T substitution at nucleotide position 227, causing the proline (P) at amino acid position 76 to be replaced by a leucine (L). 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

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;.;T;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.2

.;.;M;.;.

PhyloP100

8.0

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-9.4

.;.;D;.;.

REVEL

Uncertain

0.38

Sift

Uncertain

0.022

.;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0, 0.93

.;.;D;P;.

Vest4

0.69

MutPred

0.57

.;.;Loss of loop (P = 0.0203);.;.;

MVP

0.53

MPC

0.69

ClinPred

0.97

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.78

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over