chr19-18173940-C-G

Position:

• chr19-18173940-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006332.5(IFI30):​c.99C>G​(p.Asp33Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: IFI30 NM_006332.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.716

Genes affected

IFI30 (HGNC:5398): (IFI30 lysosomal thiol reductase) The protein encoded by this gene is a lysosomal thiol reductase that at low pH can reduce protein disulfide bonds. The enzyme is expressed constitutively in antigen-presenting cells and induced by gamma-interferon in other cell types. This enzyme has an important role in MHC class II-restricted antigen processing. [provided by RefSeq, Jul 2008]

ENSG00000268173 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09069899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFI30	NM_006332.5	c.99C>G	p.Asp33Glu	missense_variant	1/7	ENST00000407280.4	NP_006323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFI30	ENST00000407280.4	c.99C>G	p.Asp33Glu	missense_variant	1/7	1	NM_006332.5	ENSP00000384886.1
ENSG00000268173	ENST00000593731.1	n.*1535C>G		non_coding_transcript_exon_variant	19/25	2		ENSP00000471914.1
ENSG00000268173	ENST00000593731.1	n.*1535C>G		3_prime_UTR_variant	19/25	2		ENSP00000471914.1
IFI30	ENST00000597802.2	c.99C>G	p.Asp33Glu	missense_variant	2/3	3		ENSP00000470527.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399200 Hom.: 0 Cov.: 32 AF XY: 0.00000435 AC XY: 3 AN XY: 690214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000689

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 30, 2024

The c.99C>G (p.D33E) alteration is located in exon 1 (coding exon 1) of the IFI30 gene. This alteration results from a C to G substitution at nucleotide position 99, causing the aspartic acid (D) at amino acid position 33 to be replaced by a glutamic acid (E). 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	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.8
DANN	Benign	0.94
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.36	.;N
REVEL	Benign	0.041
Sift	Benign	0.11	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.95	.;P
Vest4		0.14
MutPred		0.33		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.24
MPC		0.020
ClinPred		0.11	T
GERP RS		0.47
Varity_R		0.16
gMVP		0.23

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: rs999291819; hg19: chr19-18284750;