rs769757979

Variant names:

• chr17-43013574-C-A
• rs769757979
• NM_001330230.2:c.474C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-43013574-C-A
• chr17-43013574-C-G
• chr17-43013574-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001330230.2(IFI35):​c.474C>A​(p.Phe158Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F158Y) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: IFI35 NM_001330230.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 0 publications found

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]

VAT1 (HGNC:16919): (vesicle amine transport 1) Synaptic vesicles are responsible for regulating the storage and release of neurotransmitters in the nerve terminal. The protein encoded by this gene is an abundant integral membrane protein of cholinergic synaptic vesicles and is thought to be involved in vesicular transport. It belongs to the quinone oxidoreductase subfamily of zinc-containing alcohol dehydrogenase proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330230.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFI35	NM_001330230.2	MANE Select	c.474C>A	p.Phe158Leu	missense	Exon 5 of 7	NP_001317159.1	P80217-1
	IFI35	NM_005533.5		c.480C>A	p.Phe160Leu	missense	Exon 5 of 7	NP_005524.2	P80217-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFI35	ENST00000415816.7	TSL:5 MANE Select	c.474C>A	p.Phe158Leu	missense	Exon 5 of 7	ENSP00000394579.3	P80217-1
	IFI35	ENST00000438323.2	TSL:1	c.480C>A	p.Phe160Leu	missense	Exon 5 of 7	ENSP00000395590.2	P80217-2
	VAT1	ENST00000943217.1		c.*1+2486G>T		intron	N/A	ENSP00000613276.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 39

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Benign	0.081	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.64
MutPred		0.57		Gain of ubiquitination at K154 (P = 0.0945)
MVP		0.29
MPC		0.43
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.44
gMVP		0.62

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

Other links and lift over

dbSNP: rs769757979; hg19: chr17-41165591;