17-43013548-G-C

Variant names:

• chr17-43013548-G-C
• rs1192224414
• NM_001330230.2:c.448G>C

Variant summary

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

The NM_001330230.2(IFI35):​c.448G>C​(p.Glu150Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E150V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IFI35 NM_001330230.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.177

Genes affected

IFI35 (HGNC:5399): (interferon induced protein 35) Enables identical protein binding activity. Involved in several processes, including macrophage activation involved in immune response; positive regulation of defense response; and regulation of signal transduction. Located in several cellular components, including cytosol; extracellular space; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.069221824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFI35	NM_001330230.2	c.448G>C	p.Glu150Gln	missense_variant	Exon 5 of 7	ENST00000415816.7	NP_001317159.1
IFI35	NM_005533.5	c.454G>C	p.Glu152Gln	missense_variant	Exon 5 of 7		NP_005524.2
IFI35	XM_017024584.2	c.394G>C	p.Glu132Gln	missense_variant	Exon 5 of 7		XP_016880073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFI35	ENST00000415816.7	c.448G>C	p.Glu150Gln	missense_variant	Exon 5 of 7	5	NM_001330230.2	ENSP00000394579.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461854 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

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: 0.00000360

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

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.454G>C (p.E152Q) alteration is located in exon 5 (coding exon 5) of the IFI35 gene. This alteration results from a G to C substitution at nucleotide position 454, causing the glutamic acid (E) at amino acid position 152 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.0039	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.76	N;N
REVEL	Benign	0.030
Sift	Benign	0.43	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0090	B;.
Vest4		0.15
MutPred		0.48		Loss of ubiquitination at K154 (P = 0.0508);.;
MVP		0.39
MPC		0.067
ClinPred		0.051	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.35

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: rs1192224414; hg19: chr17-41165565;