14-23476374-A-C

Position:

• chr14-23476374-A-C

Variant summary

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

The NM_001042635.2(NGDN):​c.680A>C​(p.His227Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NGDN NM_001042635.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

Genes affected

NGDN (HGNC:20271): (neuroguidin) Neuroguidin is an EIF4E (MIM 133440)-binding protein that interacts with CPEB (MIM 607342) and functions as a translational regulatory protein during development of the vertebrate nervous system (Jung et al., 2006 [PubMed 16705177]).[supplied by OMIM, Mar 2008]

NGDN (HGNC:):

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/exons	MANE	Protein	UniProt
NGDN	NM_001042635.2	c.680A>C	p.His227Pro	missense_variant	8/11	ENST00000408901.8	NP_001036100.1
NGDN	NM_015514.2	c.680A>C	p.His227Pro	missense_variant	8/10		NP_056329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NGDN	ENST00000408901.8	c.680A>C	p.His227Pro	missense_variant	8/11	1	NM_001042635.2	ENSP00000386134.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Jul 10, 2024

The c.680A>C (p.H227P) alteration is located in exon 8 (coding exon 8) of the NGDN gene. This alteration results from a A to C substitution at nucleotide position 680, causing the histidine (H) at amino acid position 227 to be replaced by a proline (P). 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	0.23
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0087	T
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.28
Sift	Benign	0.058	T;T
Sift4G	Uncertain	0.051	T;T
Polyphen		1.0	D;D
Vest4		0.57
MutPred		0.25		Gain of catalytic residue at P226 (P = 0.0148);Gain of catalytic residue at P226 (P = 0.0148);
MVP		0.58
MPC		0.57
ClinPred		0.95	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.45

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: chr14-23945583;