11-20678049-T-G

Variant summary

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

The NM_006157.5(NELL1):c.173T>G(p.Phe58Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NELL1 NM_006157.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

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, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NELL1	NM_006157.5	c.173T>G	p.Phe58Cys	missense_variant	2/20	ENST00000357134.10
NELL1	NM_001288713.1	c.257T>G	p.Phe86Cys	missense_variant	3/21
NELL1	NM_201551.2	c.173T>G	p.Phe58Cys	missense_variant	2/19
NELL1	NM_001288714.1	c.173T>G	p.Phe58Cys	missense_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NELL1	ENST00000357134.10	c.173T>G	p.Phe58Cys	missense_variant	2/20	1	NM_006157.5	P1
NELL1	ENST00000532434.5	c.173T>G	p.Phe58Cys	missense_variant	2/19	1
NELL1	ENST00000298925.9	c.257T>G	p.Phe86Cys	missense_variant	3/21	2
NELL1	ENST00000325319.9	c.173T>G	p.Phe58Cys	missense_variant	2/19	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.173T>G (p.F58C) alteration is located in exon 2 (coding exon 2) of the NELL1 gene. This alteration results from a T to G substitution at nucleotide position 173, causing the phenylalanine (F) at amino acid position 58 to be replaced by a cysteine (C). 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	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.95	P;.;P;D
Vest4		0.76
MutPred		0.66		Gain of catalytic residue at L59 (P = 0.0189);.;Gain of catalytic residue at L59 (P = 0.0189);Gain of catalytic residue at L59 (P = 0.0189);
MVP		0.70
MPC		0.49
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.56
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: chr11-20699595;