14-24431649-A-G

Position:

• chr14-24431649-A-G

Variant summary

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

The NM_015299.3(KHNYN):​c.388A>G​(p.Met130Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,696 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KHNYN NM_015299.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

Genes affected

KHNYN (HGNC:20166): (KH and NYN domain containing) The protein encoded by this gene contains a ribonuclease NYN domain and belongs to the N4BP1 family. The protein is a cofactor for the zinc finger antiviral protein (ZAP protein) which targets viral RNA for degradation and restricts SARS-CoV-2 infection. [provided by RefSeq, Sep 2021]

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=0.36577606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHNYN	NM_015299.3	c.388A>G	p.Met130Val	missense_variant	3/8	ENST00000553935.6	NP_056114.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHNYN	ENST00000553935.6	c.388A>G	p.Met130Val	missense_variant	3/8	1	NM_015299.3	ENSP00000450799.1
KHNYN	ENST00000251343.9	c.388A>G	p.Met130Val	missense_variant	3/8	1		ENSP00000251343.5
KHNYN	ENST00000556842.5	c.388A>G	p.Met130Val	missense_variant	3/8	2		ENSP00000451106.1
KHNYN	ENST00000556510.1	c.388A>G	p.Met130Val	missense_variant	2/2	2		ENSP00000451004.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461696 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727128

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.388A>G (p.M130V) alteration is located in exon 3 (coding exon 2) of the KHNYN gene. This alteration results from a A to G substitution at nucleotide position 388, causing the methionine (M) at amino acid position 130 to be replaced by a valine (V). 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	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.76	.;.;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.8	M;M;M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.30	B;B;B;.
Vest4		0.67
MutPred		0.54		Gain of catalytic residue at F128 (P = 0.0014);Gain of catalytic residue at F128 (P = 0.0014);Gain of catalytic residue at F128 (P = 0.0014);Gain of catalytic residue at F128 (P = 0.0014);
MVP		0.61
MPC		0.88
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs890270912; hg19: chr14-24900855;