11-20678032-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006157.5(NELL1):c.156C>G(p.His52Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H52Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NELL1 NM_006157.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NELL1	NM_006157.5	c.156C>G	p.His52Gln	missense_variant	2/20	ENST00000357134.10
NELL1	NM_001288713.1	c.240C>G	p.His80Gln	missense_variant	3/21
NELL1	NM_201551.2	c.156C>G	p.His52Gln	missense_variant	2/19
NELL1	NM_001288714.1	c.156C>G	p.His52Gln	missense_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NELL1	ENST00000357134.10	c.156C>G	p.His52Gln	missense_variant	2/20	1	NM_006157.5	P1
NELL1	ENST00000532434.5	c.156C>G	p.His52Gln	missense_variant	2/19	1
NELL1	ENST00000298925.9	c.240C>G	p.His80Gln	missense_variant	3/21	2
NELL1	ENST00000325319.9	c.156C>G	p.His52Gln	missense_variant	2/19	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.156C>G (p.H52Q) alteration is located in exon 2 (coding exon 2) of the NELL1 gene. This alteration results from a C to G substitution at nucleotide position 156, causing the histidine (H) at amino acid position 52 to be replaced by a glutamine (Q). 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	0.17
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.0058
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;D;D;D
REVEL	Benign	0.20
Sift	Benign	0.083	T;T;T;T
Sift4G	Uncertain	0.053	T;D;D;D
Polyphen		0.63	P;.;B;D
Vest4		0.85
MutPred		0.44		Gain of relative solvent accessibility (P = 0.0522);.;Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);
MVP		0.57
MPC		0.46
ClinPred		0.95	D
GERP RS		3.0
Varity_R		0.29
gMVP		0.59

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

Other links and lift over

dbSNP: rs1034336276; hg19: chr11-20699578;