17-49506412-C-T

Variant names:

• chr17-49506412-C-T
• NM_002507.4:c.322C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_002507.4(NGFR):​c.322C>T​(p.Arg108Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,452,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NGFR NM_002507.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.666

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGFR	NM_002507.4	c.322C>T	p.Arg108Cys	missense_variant	Exon 3 of 6	ENST00000172229.8	NP_002498.1
NGFR-AS1	NR_103773.1	n.466G>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGFR	ENST00000172229.8	c.322C>T	p.Arg108Cys	missense_variant	Exon 3 of 6	1	NM_002507.4	ENSP00000172229.3
NGFR	ENST00000504201.1	c.40C>T	p.Arg14Cys	missense_variant	Exon 3 of 6	2		ENSP00000421731.1
NGFR-AS1	ENST00000514506.1	n.466G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
NGFR	ENST00000509200.5	c.*27C>T		downstream_gene_variant		4		ENSP00000421514.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000179 AC: 26 AN: 1452834 Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 12 AN XY: 722840

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: 0.0000234

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322C>T (p.R108C) alteration is located in exon 3 (coding exon 3) of the NGFR gene. This alteration results from a C to T substitution at nucleotide position 322, causing the arginine (R) at amino acid position 108 to be replaced by a cysteine (C). 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	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.039	D;D
Sift4G	Benign	0.074	T;T
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.55		Loss of sheet (P = 0.0228);.;
MVP		0.85
MPC		1.4
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.13
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-47583774;