14-24431641-C-A

Position:

• chr14-24431641-C-A

Variant summary

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

The NM_015299.3(KHNYN):​c.380C>A​(p.Ala127Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KHNYN NM_015299.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHNYN	NM_015299.3	c.380C>A	p.Ala127Asp	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.380C>A	p.Ala127Asp	missense_variant	3/8	1	NM_015299.3	ENSP00000450799.1
KHNYN	ENST00000251343.9	c.380C>A	p.Ala127Asp	missense_variant	3/8	1		ENSP00000251343.5
KHNYN	ENST00000556842.5	c.380C>A	p.Ala127Asp	missense_variant	3/8	2		ENSP00000451106.1
KHNYN	ENST00000556510.1	c.380C>A	p.Ala127Asp	missense_variant	2/2	2		ENSP00000451004.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Aug 02, 2021

The c.380C>A (p.A127D) alteration is located in exon 3 (coding exon 2) of the KHNYN gene. This alteration results from a C to A substitution at nucleotide position 380, causing the alanine (A) at amino acid position 127 to be replaced by an aspartic acid (D). 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	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	.;.;T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.7	M;M;M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.047	D;D;D;D
Polyphen		0.96	D;D;D;.
Vest4		0.90
MutPred		0.50		Gain of catalytic residue at L124 (P = 6e-04);Gain of catalytic residue at L124 (P = 6e-04);Gain of catalytic residue at L124 (P = 6e-04);Gain of catalytic residue at L124 (P = 6e-04);
MVP		0.75
MPC		1.1
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.71
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24900847;