NM_006157.5:c.337T>C

Variant names:

• chr11-20847584-T-C
• NM_006157.5:c.337T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006157.5(NELL1):​c.337T>C​(p.Tyr113His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,660 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NELL1 NM_006157.5 missense, splice_region
• Scores: Splicing: ADA: 0.9311
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NELL1	NM_006157.5	c.337T>C	p.Tyr113His	missense_variant, splice_region_variant	Exon 4 of 20	ENST00000357134.10	NP_006148.2
NELL1	NM_001288713.1	c.421T>C	p.Tyr141His	missense_variant, splice_region_variant	Exon 5 of 21		NP_001275642.1
NELL1	NM_201551.2	c.337T>C	p.Tyr113His	missense_variant, splice_region_variant	Exon 4 of 19		NP_963845.1
NELL1	NM_001288714.1	c.336-37860T>C		intron_variant	Intron 3 of 18		NP_001275643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NELL1	ENST00000357134.10	c.337T>C	p.Tyr113His	missense_variant, splice_region_variant	Exon 4 of 20	1	NM_006157.5	ENSP00000349654.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459660 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726056

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337T>C (p.Y113H) alteration is located in exon 4 (coding exon 4) of the NELL1 gene. This alteration results from a T to C substitution at nucleotide position 337, causing the tyrosine (Y) at amino acid position 113 to be replaced by a histidine (H). 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	Benign	0.22
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.6	.;M;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0, 0.99	.;D;D
Vest4		0.51
MutPred		0.65		.;Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		0.91
MPC		0.19
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.020		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: chr11-20869130;