15-90265776-T-G

Variant names:

• chr15-90265776-T-G
• NM_001033088.3:c.64T>G

Variant summary

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

The NM_001033088.3(NGRN):​c.64T>G​(p.Phe22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NGRN NM_001033088.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.181

Genes affected

NGRN (HGNC:18077): (neugrin, neurite outgrowth associated) Enables rRNA binding activity. Involved in positive regulation of mitochondrial translation. Located in several cellular components, including intercellular bridge; mitotic spindle; and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000261147 (HGNC:):

CIB1 (HGNC:16920): (calcium and integrin binding 1) This gene encodes a member of the EF-hand domain-containing calcium-binding superfamily. The encoded protein interacts with many other proteins, including the platelet integrin alpha-IIb-beta-3, DNA-dependent protein kinase, presenilin-2, focal adhesion kinase, p21 activated kinase, and protein kinase D. The encoded protein may be involved in cell survival and proliferation, and is associated with several disease states including cancer and Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2013]

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=0.18978062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGRN	NM_001033088.3	c.64T>G	p.Phe22Val	missense_variant	Exon 1 of 3	ENST00000379095.5	NP_001028260.2
NGRN	NR_028052.1	n.114T>G		non_coding_transcript_exon_variant	Exon 1 of 2
CIB1	NR_102428.1	n.-17A>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGRN	ENST00000379095.5	c.64T>G	p.Phe22Val	missense_variant	Exon 1 of 3	1	NM_001033088.3	ENSP00000368389.4
NGRN	ENST00000331497.3	n.118T>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
ENSG00000261147	ENST00000561573.1	n.*1789-512T>G		intron_variant	Intron 11 of 12	2		ENSP00000456615.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.64T>G (p.F22V) alteration is located in exon 1 (coding exon 1) of the NGRN gene. This alteration results from a T to G substitution at nucleotide position 64, causing the phenylalanine (F) at amino acid position 22 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.74
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.025
Sift	Benign	0.063	T
Sift4G	Uncertain	0.028	D
Polyphen		0.031	B
Vest4		0.41
MutPred		0.22		Gain of disorder (P = 0.0585);
MVP		0.19
MPC		0.11
ClinPred		0.10	T
GERP RS		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
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: chr15-90809008;