Genetic Variant NGFR:c.67-4C>T (chr17-49502059-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002507.4(NGFR):c.67-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,340,598 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 30)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

NGFR
NM_002507.4 splice_region, intron

Scores

Splicing: ADA: 0.00001529

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.316

Publications

1 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-49502059-C-T is Benign according to our data. Variant chr17-49502059-C-T is described in ClinVar as Benign. ClinVar VariationId is 736086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 275 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002507.4. 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
	NGFR	NM_002507.4	MANE Select	c.67-4C>T		splice_region intron	N/A	NP_002498.1	P08138-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NGFR	ENST00000172229.8	TSL:1 MANE Select	c.67-4C>T	splice_region intron	N/A	ENSP00000172229.3	P08138-1
NGFR	ENST00000504201.1	TSL:2	c.-216-4C>T	splice_region intron	N/A	ENSP00000421731.1	P08138-2
NGFR	ENST00000509200.5	TSL:4	c.-216-4C>T	splice_region intron	N/A	ENSP00000421514.1

Frequencies

GnomAD3 genomes

AF:

0.00191

AC:

272

AN:

142638

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00660

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000802

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000502

GnomAD2 exomes

AF:

0.000492

AC:

120

AN:

244004

AF XY:

0.000455

show subpopulations

Gnomad AFR exome

AF:

0.00624

Gnomad AMR exome

AF:

0.000572

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000246

AC:

295

AN:

1197842

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

137

AN XY:

587242

show subpopulations

African (AFR)

AF:

0.00891

AC:

238

AN:

26726

American (AMR)

AF:

0.000751

AC:

AN:

37278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17126

East Asian (EAS)

AF:

0.00

AC:

AN:

21594

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4408

European-Non Finnish (NFE)

AF:

0.00000320

AC:

AN:

936968

Other (OTH)

AF:

0.000573

AC:

AN:

43608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00193

AC:

275

AN:

142756

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

130

AN XY:

69102

show subpopulations

African (AFR)

AF:

0.00666

AC:

263

AN:

39502

American (AMR)

AF:

0.000801

AC:

AN:

13732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3364

East Asian (EAS)

AF:

0.00

AC:

AN:

4320

South Asian (SAS)

AF:

0.00

AC:

AN:

4154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65406

Other (OTH)

AF:

0.000497

AC:

AN:

2014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000906

Hom.:

Bravo

AF:

0.00223

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.4

(source)

DANN

Benign

0.67

PhyloP100

-0.32

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over