Genetic Variant NGRN:p.Leu174Phe (chr15-90271432-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001033088.3(NGRN):c.520C>T(p.Leu174Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 1,613,948 control chromosomes in the GnomAD database, including 7,348 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.073 ( 553 hom., cov: 32)

Exomes 𝑓: 0.093 ( 6795 hom. )

Consequence

NGRN
NM_001033088.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.627

Publications

17 publications found

Variant links:

Genes affected

NGRN (HGNC:18077): (neugrin, neurite outgrowth associated) Enables rRNA binding activity. Involved in positive regulation of mitochondrial translation. Located in several cellular components, including intercellular bridge; mitotic spindle; and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

NGRN links:

ENSG00000261147 (HGNC:):

ENSG00000261147 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022950768).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGRN	NM_001033088.3 link	c.520C>T	p.Leu174Phe	missense_variant	Exon 3 of 3	ENST00000379095.5	NP_001028260.2	Q9NPE2-2
NGRN	NR_028052.1 link	n.981C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NGRN	ENST00000379095.5 link	c.520C>T	p.Leu174Phe	missense_variant	Exon 3 of 3	1	NM_001033088.3	ENSP00000368389.4	Q9NPE2-2
ENSG00000261147	ENST00000561573.1 link	n.*2144C>T		non_coding_transcript_exon_variant	Exon 13 of 13	2		ENSP00000456615.1	H3BSA7
ENSG00000261147	ENST00000561573.1 link	n.*2144C>T		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000456615.1	H3BSA7
ENSG00000275674	ENST00000622269.1 link	c.80+5034C>T		intron_variant	Intron 1 of 3	3		ENSP00000479373.1	A0A087WVE0

Frequencies

GnomAD3 genomes

AF:

0.0729

AC:

11092

AN:

152118

Hom.:

549

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0183

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0941

Gnomad ASJ

AF:

0.0522

Gnomad EAS

AF:

0.0386

Gnomad SAS

AF:

0.0942

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0988

Gnomad OTH

AF:

0.0836

GnomAD2 exomes

AF:

0.0886

AC:

22236

AN:

250870

AF XY:

0.0913

show subpopulations

Gnomad AFR exome

AF:

0.0163

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.0603

Gnomad EAS exome

AF:

0.0321

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0981

Gnomad OTH exome

AF:

0.0911

GnomAD4 exome

AF:

0.0933

AC:

136446

AN:

1461712

Hom.:

6795

Cov.:

AF XY:

0.0939

AC XY:

68297

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0132

AC:

443

AN:

33472

American (AMR)

AF:

0.103

AC:

4590

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0592

AC:

1548

AN:

26134

East Asian (EAS)

AF:

0.0360

AC:

1431

AN:

39700

South Asian (SAS)

AF:

0.102

AC:

8819

AN:

86254

European-Finnish (FIN)

AF:

0.112

AC:

5973

AN:

53340

Middle Eastern (MID)

AF:

0.0690

AC:

398

AN:

5764

European-Non Finnish (NFE)

AF:

0.0973

AC:

108146

AN:

1111942

Other (OTH)

AF:

0.0844

AC:

5098

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

8337

16674

25010

33347

41684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3902

7804

11706

15608

19510

<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:

0.0730

AC:

11106

AN:

152236

Hom.:

553

Cov.:

AF XY:

0.0725

AC XY:

5397

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0182

AC:

757

AN:

41552

American (AMR)

AF:

0.0946

AC:

1444

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0522

AC:

181

AN:

3468

East Asian (EAS)

AF:

0.0387

AC:

201

AN:

5190

South Asian (SAS)

AF:

0.0947

AC:

457

AN:

4826

European-Finnish (FIN)

AF:

0.103

AC:

1091

AN:

10588

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0988

AC:

6720

AN:

68020

Other (OTH)

AF:

0.0836

AC:

177

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

514

1028

1541

2055

2569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<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:

0.0823

Hom.:

766

Bravo

AF:

0.0693

TwinsUK

AF:

0.0909

AC:

337

ALSPAC

AF:

0.0903

AC:

348

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.0982

AC:

844

ExAC

AF:

0.0877

AC:

10650

Asia WGS

AF:

0.0590

AC:

203

AN:

3478

EpiCase

AF:

0.0914

EpiControl

AF:

0.0899

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.064

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.1

PhyloP100

0.63

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.3

REVEL

Benign

0.19

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.056

MPC

0.46

ClinPred

0.023

GERP RS

3.5

Varity_R

0.17

gMVP

0.39

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over