17-43013614-C-T

Variant names:

• chr17-43013614-C-T
• rs369228705
• NM_001330230.2:c.514C>T

Variant summary

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

The NM_001330230.2(IFI35):​c.514C>T​(p.Arg172Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,932 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: IFI35 NM_001330230.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39216426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFI35	NM_001330230.2	c.514C>T	p.Arg172Trp	missense_variant	Exon 5 of 7	ENST00000415816.7	NP_001317159.1
IFI35	NM_005533.5	c.520C>T	p.Arg174Trp	missense_variant	Exon 5 of 7		NP_005524.2
IFI35	XM_017024584.2	c.460C>T	p.Arg154Trp	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.514C>T	p.Arg172Trp	missense_variant	Exon 5 of 7	5	NM_001330230.2	ENSP00000394579.3

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251292 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461848 Hom.: 0 Cov.: 39 AF XY: 0.0000344 AC XY: 25 AN XY: 727220

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74292

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.520C>T (p.R174W) alteration is located in exon 5 (coding exon 5) of the IFI35 gene. This alteration results from a C to T substitution at nucleotide position 520, causing the arginine (R) at amino acid position 174 to be replaced by a tryptophan (W). 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	0.29
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.45		Loss of sheet (P = 0.0126);.;
MVP		0.52
MPC		0.41
ClinPred		0.28	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs369228705; hg19: chr17-41165631; COSMIC: COSV99887937; COSMIC: COSV99887937;