9-27524683-T-C

Variant names:

• chr9-27524683-T-C
• rs556380931
• NM_020124.3:c.347T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020124.3(IFNK):​c.347T>C​(p.Ile116Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: IFNK NM_020124.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.109
• Publications: 0 publications found

Genes affected

IFNK (HGNC:21714): (interferon kappa) This gene encodes a member of the type I interferon family. Type I interferons are a group of related glycoproteins that play an important role in host defenses against viral infections. This protein is expressed in keratinocytes and the gene is found on chromosome 9, adjacent to the type I interferon cluster. [provided by RefSeq, Jul 2008]

MOB3B (HGNC:23825): (MOB kinase activator 3B) The protein encoded by this gene shares similarity with the yeast Mob1 protein. Yeast Mob1 binds Mps1p, a protein kinase essential for spindle pole body duplication and mitotic checkpoint regulation. This gene is located on the opposite strand as the interferon kappa precursor (IFNK) gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01566562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNK	NM_020124.3	c.347T>C	p.Ile116Thr	missense_variant	Exon 1 of 2	ENST00000276943.3	NP_064509.2
MOB3B	NM_024761.5	c.-199+4872A>G		intron_variant	Intron 1 of 3	ENST00000262244.6	NP_079037.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNK	ENST00000276943.3	c.347T>C	p.Ile116Thr	missense_variant	Exon 1 of 2	1	NM_020124.3	ENSP00000276943.2
MOB3B	ENST00000262244.6	c.-199+4872A>G		intron_variant	Intron 1 of 3	1	NM_024761.5	ENSP00000262244.5

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151986 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251308 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18 AN XY: 727222

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111974

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74352

African (AFR) AF: 0.0000723 AC: 3 AN: 41494

American (AMR) AF: 0.000262 AC: 4 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000447 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000165 AC: 2

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

Nov 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.347T>C (p.I116T) alteration is located in exon 1 (coding exon 1) of the IFNK gene. This alteration results from a T to C substitution at nucleotide position 347, causing the isoleucine (I) at amino acid position 116 to be replaced by a threonine (T). 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	0.066
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.89
DANN	Benign	0.50
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.11
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.077
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Polyphen		0.038	B
Vest4		0.037
MutPred		0.44		Loss of stability (P = 0.0059);
MVP		0.17
MPC		0.0065
ClinPred		0.072	T
GERP RS		-4.4
PromoterAI		0.036	Neutral
Varity_R		0.056
gMVP		0.062
Mutation Taster		=99/1	polymorphism

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: rs556380931; hg19: chr9-27524681;