11-20783740-G-T

Variant names:

• chr11-20783740-G-T
• rs8176785
• NM_006157.5:c.245G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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. 12/21 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. R82Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NELL1 NM_006157.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.46

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 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	UniProt
NELL1	NM_006157.5	c.245G>T	p.Arg82Leu	missense_variant	Exon 3 of 20	ENST00000357134.10	NP_006148.2
NELL1	NM_001288713.1	c.329G>T	p.Arg110Leu	missense_variant	Exon 4 of 21		NP_001275642.1
NELL1	NM_201551.2	c.245G>T	p.Arg82Leu	missense_variant	Exon 3 of 19		NP_963845.1
NELL1	NM_001288714.1	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	c.245G>T	p.Arg82Leu	missense_variant	Exon 3 of 20	1	NM_006157.5	ENSP00000349654.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461732 Hom.: 0 Cov.: 41 AF XY: 0.00000275 AC XY: 2 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	.;T;T;.
Eigen	Benign	-0.0069
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.74	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;.;M;M
PrimateAI	Benign	0.39	T
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	D
GERP RS		3.1
Varity_R		0.27
gMVP		0.57

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: rs8176785; hg19: chr11-20805286;