rs8176785

Positions:

• chr11-20783740-G-A
• chr11-20783740-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006157.5(NELL1):​c.245G>A​(p.Arg82Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 1,613,384 control chromosomes in the GnomAD database, including 449,216 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.63 (34060 hom., cov: 31)
  • Exomes 𝑓: 0.75 (415156 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.0671424E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NELL1	NM_006157.5	c.245G>A	p.Arg82Gln	missense_variant	3/20	ENST00000357134.10
NELL1	NM_001288713.1	c.329G>A	p.Arg110Gln	missense_variant	4/21
NELL1	NM_201551.2	c.245G>A	p.Arg82Gln	missense_variant	3/19
NELL1	NM_001288714.1	c.245G>A	p.Arg82Gln	missense_variant	3/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NELL1	ENST00000357134.10	c.245G>A	p.Arg82Gln	missense_variant	3/20	1	NM_006157.5	P1

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96482 AN: 151870 Hom.: 34056 Cov.: 31

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.845

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.755

Gnomad OTH AF: 0.693

GnomAD3 exomes AF: 0.747 AC: 187642 AN: 251220 Hom.: 72413 AF XY: 0.751 AC XY: 101977 AN XY: 135772

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.881

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.856

Gnomad SAS exome AF: 0.754

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.760

Gnomad OTH exome AF: 0.774

GnomAD4 exome AF: 0.749 AC: 1094656 AN: 1461396 Hom.: 415156 Cov.: 41 AF XY: 0.751 AC XY: 545969 AN XY: 727024

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.874

Gnomad4 ASJ exome AF: 0.827

Gnomad4 EAS exome AF: 0.859

Gnomad4 SAS exome AF: 0.754

Gnomad4 FIN exome AF: 0.662

Gnomad4 NFE exome AF: 0.756

Gnomad4 OTH exome AF: 0.746

GnomAD4 genome AF: 0.635 AC: 96503 AN: 151988 Hom.: 34060 Cov.: 31 AF XY: 0.638 AC XY: 47408 AN XY: 74316

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.819

Gnomad4 ASJ AF: 0.845

Gnomad4 EAS AF: 0.852

Gnomad4 SAS AF: 0.751

Gnomad4 FIN AF: 0.652

Gnomad4 NFE AF: 0.755

Gnomad4 OTH AF: 0.693

Alfa AF: 0.742 Hom.: 78210

Bravo AF: 0.634

TwinsUK AF: 0.745 AC: 2764

ALSPAC AF: 0.763 AC: 2939

ESP6500AA AF: 0.302 AC: 1331

ESP6500EA AF: 0.756 AC: 6504

ExAC AF: 0.736 AC: 89362

Asia WGS AF: 0.780 AC: 2714 AN: 3478

EpiCase AF: 0.770

EpiControl AF: 0.774

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	.;T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T;T;T
MetaRNN	Benign	8.1e-7	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;.;L;L
MutationTaster	Benign	0.58	P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.084
Sift	Benign	0.17	T;T;T;T
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		0.0070	B;.;B;B
Vest4		0.19
MPC		0.10
ClinPred		0.027	T
GERP RS		3.1
Varity_R		0.088
gMVP		0.47

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;