17-7318323-T-C

Variant names:

• chr17-7318323-T-C
• rs934174303
• NM_032442.3:c.3898A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032442.3(NEURL4):​c.3898A>G​(p.Ser1300Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NEURL4 NM_032442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07512313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEURL4	NM_032442.3	c.3898A>G	p.Ser1300Gly	missense_variant	Exon 24 of 29	ENST00000399464.7	NP_115818.2
NEURL4	NM_001005408.2	c.3892A>G	p.Ser1298Gly	missense_variant	Exon 24 of 29		NP_001005408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEURL4	ENST00000399464.7	c.3898A>G	p.Ser1300Gly	missense_variant	Exon 24 of 29	1	NM_032442.3	ENSP00000382390.2
ENSG00000261915	ENST00000575474.1	n.337A>G		non_coding_transcript_exon_variant	Exon 3 of 19	5		ENSP00000468772.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249530 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135384

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3898A>G (p.S1300G) alteration is located in exon 24 (coding exon 24) of the NEURL4 gene. This alteration results from a A to G substitution at nucleotide position 3898, causing the serine (S) at amino acid position 1300 to be replaced by a glycine (G). 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	0.058
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0050	.;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.075	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.90	N;N;.
REVEL	Benign	0.081
Sift	Benign	0.40	T;T;.
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.036
MutPred		0.24		.;Loss of glycosylation at S1300 (P = 0.0021);.;
MVP		0.068
MPC		0.48
ClinPred		0.17	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.21

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: rs934174303; hg19: chr17-7221642;