NM_006157.5:c.281A>G

Variant names:

• chr11-20783776-A-G
• NM_006157.5:c.281A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006157.5(NELL1):​c.281A>G​(p.Gln94Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NELL1 NM_006157.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21632367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NELL1	NM_006157.5	c.281A>G	p.Gln94Arg	missense_variant	Exon 3 of 20	ENST00000357134.10	NP_006148.2
NELL1	NM_001288713.1	c.365A>G	p.Gln122Arg	missense_variant	Exon 4 of 21		NP_001275642.1
NELL1	NM_201551.2	c.281A>G	p.Gln94Arg	missense_variant	Exon 3 of 19		NP_963845.1
NELL1	NM_001288714.1	c.281A>G	p.Gln94Arg	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	c.281A>G	p.Gln94Arg	missense_variant	Exon 3 of 20	1	NM_006157.5	ENSP00000349654.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.281A>G (p.Q94R) alteration is located in exon 3 (coding exon 3) of the NELL1 gene. This alteration results from a A to G substitution at nucleotide position 281, causing the glutamine (Q) at amino acid position 94 to be replaced by an arginine (R). 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	0.091
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0013	.;T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.059
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.97	.;.;L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.22	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.078	T;D;D;D
Polyphen		0.0050	B;.;B;B
Vest4		0.34
MutPred		0.45		Loss of ubiquitination at K96 (P = 0.0516);.;Loss of ubiquitination at K96 (P = 0.0516);Loss of ubiquitination at K96 (P = 0.0516);
MVP		0.49
MPC		0.092
ClinPred		0.81	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-20805322;