rs8176786

Variant names:

• chr11-20937848-C-T
• rs8176786
• NM_006157.5:c.1060C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
NELL1	NM_006157.5	c.1060C>T	p.Arg354Trp	missense_variant	Exon 10 of 20	ENST00000357134.10	NP_006148.2
NELL1	NM_001288713.1	c.1144C>T	p.Arg382Trp	missense_variant	Exon 11 of 21		NP_001275642.1
NELL1	NM_201551.2	c.1060C>T	p.Arg354Trp	missense_variant	Exon 10 of 19		NP_963845.1
NELL1	NM_001288714.1	c.889C>T	p.Arg297Trp	missense_variant	Exon 9 of 19		NP_001275643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NELL1	ENST00000357134.10	c.1060C>T	p.Arg354Trp	missense_variant	Exon 10 of 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

GnomAD2 exomes AF: 0.0449 AC: 11282 AN: 251014 AF XY: 0.0457

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 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

African (AFR) AF: 0.00774 AC: 259 AN: 33462

American (AMR) AF: 0.0236 AC: 1055 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 1423 AN: 26130

East Asian (EAS) AF: 0.0847 AC: 3361 AN: 39684

South Asian (SAS) AF: 0.0326 AC: 2815 AN: 86234

European-Finnish (FIN) AF: 0.0474 AC: 2530 AN: 53412

Middle Eastern (MID) AF: 0.0644 AC: 371 AN: 5762

European-Non Finnish (NFE) AF: 0.0493 AC: 54804 AN: 1111428

Other (OTH) AF: 0.0483 AC: 2916 AN: 60372

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

African (AFR) AF: 0.00763 AC: 317 AN: 41546

American (AMR) AF: 0.0266 AC: 407 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3470

East Asian (EAS) AF: 0.0841 AC: 436 AN: 5186

South Asian (SAS) AF: 0.0330 AC: 159 AN: 4820

European-Finnish (FIN) AF: 0.0487 AC: 516 AN: 10604

Middle Eastern (MID) AF: 0.0925 AC: 27 AN: 292

European-Non Finnish (NFE) AF: 0.0516 AC: 3511 AN: 68018

Other (OTH) AF: 0.0517 AC: 109 AN: 2110

Alfa AF: 0.0470 Hom.: 438

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
PhyloP100		2.0
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
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8176786; hg19: chr11-20959394; COSMIC: COSV54286546;