20-37301309-A-C

Position:

• chr20-37301309-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP4

The ENST00000373606.8(MANBAL):​c.46A>C​(p.Thr16Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MANBAL ENST00000373606.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.34

Genes affected

MANBAL (HGNC:15799): (mannosidase beta like) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN [when max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.40675932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANBAL	NM_001003897.2	c.46A>C	p.Thr16Pro	missense_variant	2/3	ENST00000373606.8	NP_001003897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANBAL	ENST00000373606.8	c.46A>C	p.Thr16Pro	missense_variant	2/3	1	NM_001003897.2	ENSP00000362708	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459886 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726320

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.46A>C (p.T16P) alteration is located in exon 3 (coding exon 1) of the MANBAL gene. This alteration results from a A to C substitution at nucleotide position 46, causing the threonine (T) at amino acid position 16 to be replaced by a proline (P). 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;T;.;.;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.65
MutPred		0.44		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.085
MPC		0.66
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.71
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-35929712;