17-43013497-C-T

Variant names:

• chr17-43013497-C-T
• rs149709197
• NM_001330230.2:c.397C>T

Variant summary

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

The NM_001330230.2(IFI35):​c.397C>T​(p.Arg133Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,613,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R133Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: IFI35 NM_001330230.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.103

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=0.08894828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFI35	NM_001330230.2	c.397C>T	p.Arg133Trp	missense_variant	Exon 5 of 7	ENST00000415816.7	NP_001317159.1
IFI35	NM_005533.5	c.403C>T	p.Arg135Trp	missense_variant	Exon 5 of 7		NP_005524.2
IFI35	XM_017024584.2	c.343C>T	p.Arg115Trp	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.397C>T	p.Arg133Trp	missense_variant	Exon 5 of 7	5	NM_001330230.2	ENSP00000394579.3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 250778 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135480

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000190 AC: 278 AN: 1461714 Hom.: 0 Cov.: 39 AF XY: 0.000184 AC XY: 134 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74312

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000232 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.403C>T (p.R135W) 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 403, causing the arginine (R) at amino acid position 135 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	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.023
Sift	Benign	0.047	D;D
Sift4G	Benign	0.067	T;T
Polyphen		0.0090	B;.
Vest4		0.21
MVP		0.31
MPC		0.077
ClinPred		0.040	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.64

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: rs149709197; hg19: chr17-41165514; COSMIC: COSV55896733; COSMIC: COSV55896733;