5-90474001-C-T

Position:

• chr5-90474001-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001370354.1(POLR3G):​c.-361C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLR3G NM_001370354.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

Genes affected

MBLAC2 (HGNC:33711): (metallo-beta-lactamase domain containing 2) Enables palmitoyl-CoA hydrolase activity. Located in endoplasmic reticulum membrane and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

POLR3G (HGNC:30075): (RNA polymerase III subunit G) Enables chromatin binding activity. Involved in positive regulation of innate immune response; positive regulation of interferon-beta production; and transcription by RNA polymerase III. Acts upstream of or within cell population proliferation. Located in cytosol and nuclear body. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBLAC2	NM_203406.2	c.292G>A	p.Val98Met	missense_variant	1/2	ENST00000316610.7	NP_981951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBLAC2	ENST00000316610.7	c.292G>A	p.Val98Met	missense_variant	1/2	1	NM_203406.2	ENSP00000314776.6
MBLAC2	ENST00000514906.1	c.292G>A	p.Val98Met	missense_variant	1/1	6		ENSP00000425600.1
POLR3G	ENST00000512239.1	c.-44+2075C>T		intron_variant		5		ENSP00000424970.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446374 Hom.: 0 Cov.: 36 AF XY: 0.00000139 AC XY: 1 AN XY: 718162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-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

Feb 27, 2024

The c.292G>A (p.V98M) alteration is located in exon 1 (coding exon 1) of the MBLAC2 gene. This alteration results from a G to A substitution at nucleotide position 292, causing the valine (V) at amino acid position 98 to be replaced by a methionine (M). 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	0.65
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.55	N;N
REVEL	Uncertain	0.44
Sift	Benign	0.14	T;T
Sift4G	Benign	0.093	T;T
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.53		Loss of stability (P = 0.0708);Loss of stability (P = 0.0708);
MVP		0.52
MPC		1.1
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.49
gMVP		0.81

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: rs1179934133; hg19: chr5-89769818;