16-4609752-G-T

Variant names:

• chr16-4609752-G-T
• rs1369678556
• NM_145253.3:c.415C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145253.3(UBALD1):​c.415C>A​(p.Pro139Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000517 in 1,352,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: UBALD1 NM_145253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

Genes affected

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

ACMG classification

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=0.12286082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBALD1	NM_145253.3	c.415C>A	p.Pro139Thr	missense_variant	Exon 3 of 3	ENST00000283474.12	NP_660296.1
UBALD1	NM_001330467.2	c.340C>A	p.Pro114Thr	missense_variant	Exon 3 of 3		NP_001317396.1
UBALD1	NM_001411032.1	c.*231C>A		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	c.415C>A	p.Pro139Thr	missense_variant	Exon 3 of 3	1	NM_145253.3	ENSP00000283474.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000661 AC: 1 AN: 151360 AF XY: 0.00

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: 0.0000138

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000517 AC: 7 AN: 1352808 Hom.: 0 Cov.: 32 AF XY: 0.00000453 AC XY: 3 AN XY: 662920

African (AFR) AF: 0.00 AC: 0 AN: 29270

American (AMR) AF: 0.00 AC: 0 AN: 27598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19396

East Asian (EAS) AF: 0.00 AC: 0 AN: 37344

South Asian (SAS) AF: 0.00 AC: 0 AN: 69612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4748

European-Non Finnish (NFE) AF: 0.00000659 AC: 7 AN: 1062536

Other (OTH) AF: 0.00 AC: 0 AN: 55444

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.415C>A (p.P139T) alteration is located in exon 3 (coding exon 3) of the UBALD1 gene. This alteration results from a C to A substitution at nucleotide position 415, causing the proline (P) at amino acid position 139 to be replaced by a threonine (T). 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	0.070
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.0049	.;.;T;T;.
Eigen	Benign	-0.066
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.90	.;.;L;.;.
PhyloP100		3.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	.;.;N;.;.
REVEL	Benign	0.026
Sift	Benign	0.23	.;.;T;.;.
Sift4G	Uncertain	0.050	T;T;T;T;T
Polyphen		0.24	.;.;B;B;.
Vest4		0.35
MutPred		0.25		.;.;Gain of phosphorylation at P139 (P = 0.0252);.;.;
MVP		0.11
MPC		0.18
ClinPred		0.43	T
GERP RS		4.2
Varity_R		0.10
gMVP		0.26
Mutation Taster		=73/27	polymorphism

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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Other links and lift over

dbSNP: rs1369678556; hg19: chr16-4659753;