rs8176786

Positions:

• chr11-20937848-C-T

Variant summary

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

The NM_006157.5(NELL1):​c.1060C>T​(p.Arg354Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,613,442 control chromosomes in the GnomAD database, including 1,955 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.

• Frequency:
  • Genomes: 𝑓 0.038 (158 hom., cov: 33)
  • Exomes 𝑓: 0.048 (1797 hom.)
• Consequence: NELL1 NM_006157.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002621591).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NELL1	NM_006157.5	c.1060C>T	p.Arg354Trp	missense_variant	10/20	ENST00000357134.10	NP_006148.2
NELL1	NM_001288713.1	c.1144C>T	p.Arg382Trp	missense_variant	11/21		NP_001275642.1
NELL1	NM_201551.2	c.1060C>T	p.Arg354Trp	missense_variant	10/19		NP_963845.1
NELL1	NM_001288714.1	c.889C>T	p.Arg297Trp	missense_variant	9/19		NP_001275643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NELL1	ENST00000357134.10	c.1060C>T	p.Arg354Trp	missense_variant	10/20	1	NM_006157.5	ENSP00000349654.5

Frequencies

GnomAD3 genomes AF: 0.0381 AC: 5794 AN: 152128 Hom.: 158 Cov.: 33

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.0267

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.0841

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.0487

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0517

GnomAD3 exomes AF: 0.0449 AC: 11282 AN: 251014 Hom.: 347 AF XY: 0.0457 AC XY: 6194 AN XY: 135636

Gnomad AFR exome AF: 0.00622

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0529

Gnomad EAS exome AF: 0.0856

Gnomad SAS exome AF: 0.0324

Gnomad FIN exome AF: 0.0477

Gnomad NFE exome AF: 0.0523

Gnomad OTH exome AF: 0.0532

GnomAD4 exome AF: 0.0476 AC: 69534 AN: 1461196 Hom.: 1797 Cov.: 30 AF XY: 0.0476 AC XY: 34615 AN XY: 726940

Gnomad4 AFR exome AF: 0.00774

Gnomad4 AMR exome AF: 0.0236

Gnomad4 ASJ exome AF: 0.0545

Gnomad4 EAS exome AF: 0.0847

Gnomad4 SAS exome AF: 0.0326

Gnomad4 FIN exome AF: 0.0474

Gnomad4 NFE exome AF: 0.0493

Gnomad4 OTH exome AF: 0.0483

GnomAD4 genome AF: 0.0380 AC: 5792 AN: 152246 Hom.: 158 Cov.: 33 AF XY: 0.0373 AC XY: 2779 AN XY: 74440

Gnomad4 AFR AF: 0.00763

Gnomad4 AMR AF: 0.0266

Gnomad4 ASJ AF: 0.0464

Gnomad4 EAS AF: 0.0841

Gnomad4 SAS AF: 0.0330

Gnomad4 FIN AF: 0.0487

Gnomad4 NFE AF: 0.0516

Gnomad4 OTH AF: 0.0517

Alfa AF: 0.0493 Hom.: 347

Bravo AF: 0.0362

TwinsUK AF: 0.0494 AC: 183

ALSPAC AF: 0.0506 AC: 195

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0507 AC: 436

ExAC AF: 0.0456 AC: 5530

Asia WGS AF: 0.0480 AC: 167 AN: 3478

EpiCase AF: 0.0515

EpiControl AF: 0.0508

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	.;T;T;.
Eigen	Benign	-0.021
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;.;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.99	D;.;B;B
Vest4		0.45
MPC		0.088
ClinPred		0.016	T
GERP RS		4.3
Varity_R		0.16
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8176786; hg19: chr11-20959394; COSMIC: COSV54286546;