15-90271207-C-G

Variant names:

• chr15-90271207-C-G
• rs1325908732
• NM_001033088.3:c.295C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001033088.3(NGRN):​c.295C>G​(p.Pro99Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,222 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 Likely benign (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: NGRN NM_001033088.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22

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]

ENSG00000275674 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08782774).
• BP6: Variant 15-90271207-C-G is Benign according to our data. Variant chr15-90271207-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3299614.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGRN	NM_001033088.3	c.295C>G	p.Pro99Ala	missense_variant	Exon 3 of 3	ENST00000379095.5	NP_001028260.2
NGRN	NR_028052.1	n.756C>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGRN	ENST00000379095.5	c.295C>G	p.Pro99Ala	missense_variant	Exon 3 of 3	1	NM_001033088.3	ENSP00000368389.4
ENSG00000275674	ENST00000622269.1	c.80+4809C>G		intron_variant	Intron 1 of 3	3		ENSP00000479373.1
ENSG00000261147	ENST00000561573.1	n.*1919C>G		non_coding_transcript_exon_variant	Exon 13 of 13	2		ENSP00000456615.1
ENSG00000261147	ENST00000561573.1	n.*1919C>G		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000456615.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 20, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.82
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.3	N
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.056
Sift	Benign	0.61	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.57		Loss of loop (P = 0.0128);
MVP		0.29
MPC		0.081
ClinPred		0.27	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.061
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1325908732; hg19: chr15-90814439;