Genetic Variant NM_006157.5:c.154C>T (chr11-20678030-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006157.5(NELL1):c.154C>T(p.His52Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000248 in 1,614,022 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 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

NELL1
NM_006157.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.70

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19619551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NELL1	NM_006157.5 link	c.154C>T	p.His52Tyr	missense_variant	Exon 2 of 20	ENST00000357134.10	NP_006148.2	Q92832-1K9UUD5
NELL1	NM_001288713.1 link	c.238C>T	p.His80Tyr	missense_variant	Exon 3 of 21		NP_001275642.1	Q92832J3KNC5K9UUD5B3KXR2
NELL1	NM_201551.2 link	c.154C>T	p.His52Tyr	missense_variant	Exon 2 of 19		NP_963845.1	Q92832-2K9UUD5
NELL1	NM_001288714.1 link	c.154C>T	p.His52Tyr	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.154C>T	p.His52Tyr	missense_variant	Exon 2 of 20	1	NM_006157.5	ENSP00000349654.5	Q92832-1
NELL1	ENST00000532434.5 link	c.154C>T	p.His52Tyr	missense_variant	Exon 2 of 19	1		ENSP00000437170.1	Q92832-2
NELL1	ENST00000298925.9 link	c.238C>T	p.His80Tyr	missense_variant	Exon 3 of 21	2		ENSP00000298925.5	J3KNC5
NELL1	ENST00000325319.9 link	c.154C>T	p.His52Tyr	missense_variant	Exon 2 of 19	2		ENSP00000317837.5	F5H6I3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000350

AC:

AN:

251394

Hom.:

AF XY:

0.000375

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000254

AC:

372

AN:

1461814

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

190

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00237

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000245

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000191

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000343

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000655

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.154C>T (p.H52Y) alteration is located in exon 2 (coding exon 2) of the NELL1 gene. This alteration results from a C to T substitution at nucleotide position 154, causing the histidine (H) at amino acid position 52 to be replaced by a tyrosine (Y). 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

0.094

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

.;T;T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.7

.;.;M;M

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.0

N;D;D;N

REVEL

Benign

0.27

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Uncertain

0.014

D;D;D;D

Polyphen

0.92

P;.;P;D

Vest4

0.85

MVP

0.74

MPC

0.49

ClinPred

0.47

GERP RS

5.2

Varity_R

0.34

gMVP

0.62

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