Genetic Variant NM_006157.5:c.124A>G (chr11-20678000-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006157.5(NELL1):c.124A>G(p.Thr42Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

NELL1
NM_006157.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36052832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NELL1	NM_006157.5 link	c.124A>G	p.Thr42Ala	missense_variant	Exon 2 of 20	ENST00000357134.10	NP_006148.2	Q92832-1K9UUD5
NELL1	NM_001288713.1 link	c.208A>G	p.Thr70Ala	missense_variant	Exon 3 of 21		NP_001275642.1	Q92832J3KNC5K9UUD5B3KXR2
NELL1	NM_201551.2 link	c.124A>G	p.Thr42Ala	missense_variant	Exon 2 of 19		NP_963845.1	Q92832-2K9UUD5
NELL1	NM_001288714.1 link	c.124A>G	p.Thr42Ala	missense_variant	Exon 2 of 19		NP_001275643.1	Q92832F5H6I3K9UUD5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NELL1	ENST00000357134.10 link	c.124A>G	p.Thr42Ala	missense_variant	Exon 2 of 20	1	NM_006157.5	ENSP00000349654.5	Q92832-1
NELL1	ENST00000532434.5 link	c.124A>G	p.Thr42Ala	missense_variant	Exon 2 of 19	1		ENSP00000437170.1	Q92832-2
NELL1	ENST00000298925.9 link	c.208A>G	p.Thr70Ala	missense_variant	Exon 3 of 21	2		ENSP00000298925.5	J3KNC5
NELL1	ENST00000325319.9 link	c.124A>G	p.Thr42Ala	missense_variant	Exon 2 of 19	2		ENSP00000317837.5	F5H6I3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.124A>G (p.T42A) alteration is located in exon 2 (coding exon 2) of the NELL1 gene. This alteration results from a A to G substitution at nucleotide position 124, causing the threonine (T) at amino acid position 42 to be replaced by an alanine (A). 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

0.18

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

.;T;T;.

Eigen

Benign

0.060

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

T;T;T;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.6

.;.;M;M

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.55

T;T;T;T

Polyphen

0.077

B;.;B;B

Vest4

0.55

MutPred

0.40

Loss of stability (P = 0.0486);.;Loss of stability (P = 0.0486);Loss of stability (P = 0.0486);

MVP

0.65

MPC

0.10

ClinPred

0.67

GERP RS

5.0

Varity_R

0.13

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over