19-29527211-C-A

Variant names:

• chr19-29527211-C-A
• rs763904112
• NM_001146339.2:c.83C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001384641.1(VSTM2B):​c.-56C>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000717 in 1,395,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: VSTM2B NM_001384641.1 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.3099
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.03
• Publications: 0 publications found

Genes affected

VSTM2B (HGNC:33595): (V-set and transmembrane domain containing 2B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

VSTM2B-DT (HGNC:27615): (VSTM2B divergent transcript)

LOC124904683 (HGNC:):

ACMG classification

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, 0.914

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384641.1. 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
	VSTM2B	NM_001146339.2	MANE Select	c.83C>A	p.Ala28Asp	missense splice_region	Exon 2 of 5	NP_001139811.1	A6NLU5
	VSTM2B	NM_001384641.1		c.-56C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001371570.1
	VSTM2B	NM_001384642.1		c.-56C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001371571.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSTM2B	ENST00000335523.8	TSL:5 MANE Select	c.83C>A	p.Ala28Asp	missense splice_region	Exon 2 of 5	ENSP00000335038.6	A6NLU5
	VSTM2B	ENST00000915703.1		c.83C>A	p.Ala28Asp	missense splice_region	Exon 3 of 7	ENSP00000585762.1
	VSTM2B	ENST00000952478.1		c.83C>A	p.Ala28Asp	missense splice_region	Exon 2 of 6	ENSP00000622537.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395582 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 688222

⚠️ 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: 31336

American (AMR) AF: 0.00 AC: 0 AN: 35560

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25074

East Asian (EAS) AF: 0.00 AC: 0 AN: 35550

South Asian (SAS) AF: 0.00 AC: 0 AN: 78766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077570

Other (OTH) AF: 0.00 AC: 0 AN: 57872

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.73		Gain of relative solvent accessibility (P = 0.0098)
MVP		0.27
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.83
gMVP		0.79
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.31
dbscSNV1_RF	Benign	0.49
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: rs763904112; hg19: chr19-30018118;