16-4609981-C-T

Variant names:

• chr16-4609981-C-T
• rs1355901569
• NM_145253.3:c.186G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_145253.3(UBALD1):​c.186G>A​(p.Met62Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000635 in 1,573,906 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: UBALD1 NM_145253.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBALD1	NM_145253.3	c.186G>A	p.Met62Ile	missense_variant, splice_region_variant	Exon 3 of 3	ENST00000283474.12	NP_660296.1
UBALD1	NM_001411032.1	c.*2G>A		splice_region_variant	Exon 3 of 3		NP_001397961.1
UBALD1	NM_001411032.1	c.*2G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001397961.1
UBALD1	NM_001330467.2	c.184-73G>A		intron_variant	Intron 2 of 2		NP_001317396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBALD1	ENST00000283474.12	c.186G>A	p.Met62Ile	missense_variant, splice_region_variant	Exon 3 of 3	1	NM_145253.3	ENSP00000283474.6

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151438 Hom.: 0 Cov.: 31

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: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000492 AC: 7 AN: 1422468 Hom.: 0 Cov.: 31 AF XY: 0.00000426 AC XY: 3 AN XY: 704360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000550

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151438 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73926

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.186G>A (p.M62I) alteration is located in exon 3 (coding exon 3) of the UBALD1 gene. This alteration results from a G to A substitution at nucleotide position 186, causing the methionine (M) at amino acid position 62 to be replaced by an isoleucine (I). 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	0.82
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	.;.;T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.45	T;T;T;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.4	.;.;L;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	.;.;D;.;.
REVEL	Benign	0.25
Sift	Benign	0.041	.;.;D;.;.
Sift4G	Uncertain	0.030	D;T;T;D;D
Polyphen		0.29, 0.95	.;.;B;P;.
Vest4		0.54
MutPred		0.31		.;.;Gain of sheet (P = 0.0344);.;.;
MVP		0.47
MPC		0.24
ClinPred		0.96	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.61

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: rs1355901569; hg19: chr16-4659982;