17-49506655-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002507.4(NGFR):c.565G>C(p.Glu189Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,365,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NGFR NM_002507.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

Genes affected

NGFR (HGNC:7809): (nerve growth factor receptor) Nerve growth factor receptor contains an extracellular domain containing four 40-amino acid repeats with 6 cysteine residues at conserved positions followed by a serine/threonine-rich region, a single transmembrane domain, and a 155-amino acid cytoplasmic domain. The cysteine-rich region contains the nerve growth factor binding domain. [provided by RefSeq, Jul 2008]

NGFR-AS1 (HGNC:55555): (NGFR antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18603322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NGFR	NM_002507.4	c.565G>C	p.Glu189Gln	missense_variant	3/6	ENST00000172229.8
NGFR-AS1	NR_103773.1	n.378-155C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NGFR	ENST00000172229.8	c.565G>C	p.Glu189Gln	missense_variant	3/6	1	NM_002507.4	P1
NGFR-AS1	ENST00000514506.1	n.378-155C>G		intron_variant, non_coding_transcript_variant		2
NGFR	ENST00000504201.1	c.283G>C	p.Glu95Gln	missense_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1365846 Hom.: 0 Cov.: 34 AF XY: 0.00000299 AC XY: 2 AN XY: 669122

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: 0.00000188

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

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

Oct 26, 2022

The c.565G>C (p.E189Q) alteration is located in exon 3 (coding exon 3) of the NGFR gene. This alteration results from a G to C substitution at nucleotide position 565, causing the glutamic acid (E) at amino acid position 189 to be replaced by a glutamine (Q). 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	0.094
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.65	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.45	N;N
REVEL	Benign	0.17
Sift	Benign	0.39	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0020	B;.
Vest4		0.22
MutPred		0.27		Gain of MoRF binding (P = 0.0786);.;
MVP		0.75
MPC		0.52
ClinPred		0.63	D
GERP RS		4.8
Varity_R		0.077
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs1597862259; hg19: chr17-47584017;