3-42601014-C-A

Variant names:

• chr3-42601014-C-A
• rs1190657861
• NM_005385.4:c.8C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005385.4(NKTR):​c.8C>A​(p.Ala3Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,424,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NKTR NM_005385.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• Publications: 0 publications found

Genes affected

NKTR (HGNC:7833): (natural killer cell triggering receptor) This gene encodes a membrane-anchored protein with a hydrophobic amino terminal domain and a cyclophilin-like PPIase domain. It is present on the surface of natural killer cells and facilitates their binding to targets. Its expression is regulated by IL2 activation of the cells. [provided by RefSeq, Jul 2008]

SEC22C (HGNC:16828): (SEC22 homolog C, vesicle trafficking protein) This gene encodes a member of the SEC22 family of vesicle trafficking proteins. The encoded protein is localized to the endoplasmic reticulum and may play a role in the early stages of ER-Golgi protein trafficking. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16654229).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005385.4. 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
	NKTR	NM_005385.4	MANE Select	c.8C>A	p.Ala3Glu	missense	Exon 2 of 17	NP_005376.2
	NKTR	NM_001349124.2		c.8C>A	p.Ala3Glu	missense	Exon 2 of 17	NP_001336053.1
	NKTR	NM_001349125.2		c.-808C>A		5_prime_UTR	Exon 2 of 19	NP_001336054.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKTR	ENST00000232978.13	TSL:1 MANE Select	c.8C>A	p.Ala3Glu	missense	Exon 2 of 17	ENSP00000232978.8	P30414
	NKTR	ENST00000459950.1	TSL:1	n.92C>A		non_coding_transcript_exon	Exon 2 of 2
	NKTR	ENST00000937553.1		c.8C>A	p.Ala3Glu	missense	Exon 2 of 17	ENSP00000607612.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1424360 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 706440

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

African (AFR) AF: 0.00 AC: 0 AN: 31634

American (AMR) AF: 0.00 AC: 0 AN: 39710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25314

East Asian (EAS) AF: 0.00 AC: 0 AN: 37024

South Asian (SAS) AF: 0.00 AC: 0 AN: 80858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4084

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1096504

Other (OTH) AF: 0.00 AC: 0 AN: 58870

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.010
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.87	L
PhyloP100		1.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Uncertain	0.029	D
Sift4G	Benign	0.12	T
Polyphen		0.95	P
Vest4		0.48
MutPred		0.28		Gain of disorder (P = 0.0269)
MVP		0.29
MPC		1.2
ClinPred		0.89	D
GERP RS		5.2
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.45
gMVP		0.29
Mutation Taster		=76/24	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: rs1190657861; hg19: chr3-42642506;