16-4609981-C-A

Variant names:

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

Variant summary

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

The NM_145253.3(UBALD1):​c.186G>T​(p.Met62Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000703 in 1,422,468 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: UBALD1 NM_145253.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.04
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145253.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBALD1	NM_145253.3	MANE Select	c.186G>T	p.Met62Ile	missense splice_region	Exon 3 of 3	NP_660296.1	Q8TB05-1
	UBALD1	NM_001411032.1		c.*2G>T		splice_region	Exon 3 of 3	NP_001397961.1	K7EKR5
	UBALD1	NM_001411032.1		c.*2G>T		3_prime_UTR	Exon 3 of 3	NP_001397961.1	K7EKR5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBALD1	ENST00000283474.12	TSL:1 MANE Select	c.186G>T	p.Met62Ile	missense splice_region	Exon 3 of 3	ENSP00000283474.6	Q8TB05-1
	UBALD1	ENST00000590891.1	TSL:6	c.291G>T	p.Met97Ile	missense	Exon 1 of 1	ENSP00000465706.1	Q8TB05-2
	UBALD1	ENST00000591401.5	TSL:5	c.123G>T	p.Met41Ile	missense splice_region	Exon 2 of 2	ENSP00000467671.1	K7EQ49

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422468 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 704360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32952

American (AMR) AF: 0.00 AC: 0 AN: 40872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24216

East Asian (EAS) AF: 0.00 AC: 0 AN: 38990

South Asian (SAS) AF: 0.00 AC: 0 AN: 81336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090308

Other (OTH) AF: 0.00 AC: 0 AN: 58840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.59
Sift	Benign	0.041	D
Sift4G	Uncertain	0.030	D
Polyphen		0.29	B
Vest4		0.54
MutPred		0.31		Gain of sheet (P = 0.0344)
MVP		0.47
MPC		0.24
ClinPred		0.97	D
GERP RS		4.1
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

Other links and lift over

dbSNP: rs1355901569; hg19: chr16-4659982;