Genetic Variant NM_006157.5:c.245G>T (chr11-20783740-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006157.5(NELL1):c.245G>T(p.Arg82Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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. R82G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NELL1
NM_006157.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.46

Publications

35 publications found

Variant links:

Genes affected

NELL1 (HGNC:7750): (neural EGFL like 1) This gene encodes a cytoplasmic protein that contains epidermal growth factor (EGF)-like repeats. The encoded heterotrimeric protein may be involved in cell growth regulation and differentiation. A similar protein in rodents is involved in craniosynostosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

NELL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.744

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NELL1	NM_006157.5 link	c.245G>T	p.Arg82Leu	missense_variant	Exon 3 of 20	ENST00000357134.10	NP_006148.2
NELL1	NM_001288713.1 link	c.329G>T	p.Arg110Leu	missense_variant	Exon 4 of 21		NP_001275642.1
NELL1	NM_201551.2 link	c.245G>T	p.Arg82Leu	missense_variant	Exon 3 of 19		NP_963845.1
NELL1	NM_001288714.1 link	c.245G>T	p.Arg82Leu	missense_variant	Exon 3 of 19		NP_001275643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NELL1	ENST00000357134.10 link	c.245G>T	p.Arg82Leu	missense_variant	Exon 3 of 20	1	NM_006157.5	ENSP00000349654.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727172

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111906

Other (OTH)

AF:

0.00

AC:

AN:

60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

101495

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

.;T;T;.

Eigen

Benign

-0.0069

Eigen_PC

Benign

0.054

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.74

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

.;.;M;M

PhyloP100

3.5

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Benign

0.13

Sift

Uncertain

0.011

D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.49

P;.;B;P

Vest4

0.71

MutPred

0.56

Loss of catalytic residue at R82 (P = 0.0431);.;Loss of catalytic residue at R82 (P = 0.0431);Loss of catalytic residue at R82 (P = 0.0431);

MVP

0.48

MPC

0.15

ClinPred

0.99

GERP RS

3.1

Varity_R

0.27

gMVP

0.57

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over