17-7316322-C-T

Variant names:

• chr17-7316322-C-T
• rs752623474
• NM_032442.3:c.4490G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032442.3(NEURL4):​c.4490G>A​(p.Arg1497Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,611,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NEURL4 NM_032442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15
• Publications: 2 publications found

Genes affected

NEURL4 (HGNC:34410): (neuralized E3 ubiquitin protein ligase 4) The protein encoded by this gene is predicted and it includes two isoforms resulting from two alternatively spliced transcript variants. [provided by RefSeq, Jul 2008]

ENSG00000261915 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09225032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEURL4	NM_032442.3	c.4490G>A	p.Arg1497Gln	missense_variant	Exon 29 of 29	ENST00000399464.7	NP_115818.2
NEURL4	NM_001005408.2	c.4484G>A	p.Arg1495Gln	missense_variant	Exon 29 of 29		NP_001005408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEURL4	ENST00000399464.7	c.4490G>A	p.Arg1497Gln	missense_variant	Exon 29 of 29	1	NM_032442.3	ENSP00000382390.2
ENSG00000261915	ENST00000575474.1	n.929G>A		non_coding_transcript_exon_variant	Exon 8 of 19	5		ENSP00000468772.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248280 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459434 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 725930

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4430

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111352

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4490G>A (p.R1497Q) alteration is located in exon 29 (coding exon 29) of the NEURL4 gene. This alteration results from a G to A substitution at nucleotide position 4490, causing the arginine (R) at amino acid position 1497 to be replaced by a glutamine (Q). 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	0.093
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0057	.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	.;N;.
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.52	N;N;.
REVEL	Benign	0.044
Sift	Benign	0.40	T;T;.
Sift4G	Benign	0.35	T;T;T
Polyphen		0.086	B;B;.
Vest4		0.078
MutPred		0.28		.;Loss of MoRF binding (P = 0.0227);.;
MVP		0.043
MPC		0.63
ClinPred		0.36	T
GERP RS		4.6
Varity_R		0.095
gMVP		0.29
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs752623474; hg19: chr17-7219641; COSMIC: COSV59747822; COSMIC: COSV59747822;