Genetic Variant LONRF3:p.Pro13Pro (chrX-118974819-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001031855.3(LONRF3):c.39C>T(p.Pro13Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,206,837 control chromosomes in the GnomAD database, including 1 homozygotes. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000073 ( 1 hom. 22 hem. )

Consequence

LONRF3
NM_001031855.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.169

Variant links:

Genes affected

LONRF3 (HGNC:21152): (LON peptidase N-terminal domain and ring finger 3) The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. Multiple alternatively spliced transcript variants have been suggested, but their full length natures are not clear. [provided by RefSeq, Jul 2008]

LONRF3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant X-118974819-C-T is Benign according to our data. Variant chrX-118974819-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2661279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.169 with no splicing effect.

BS2

High Hemizygotes in GnomAdExome4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LONRF3	NM_001031855.3 link	c.39C>T	p.Pro13Pro	synonymous_variant	Exon 1 of 11	ENST00000371628.8	NP_001027026.1	Q496Y0-1A8K2D3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LONRF3	ENST00000371628.8 link	c.39C>T	p.Pro13Pro	synonymous_variant	Exon 1 of 11	1	NM_001031855.3	ENSP00000360690.3	Q496Y0-1
LONRF3	ENST00000304778.11 link	c.39C>T	p.Pro13Pro	synonymous_variant	Exon 1 of 10	1		ENSP00000307732.7	Q496Y0-2
LONRF3	ENST00000481285.5 link	n.39C>T		non_coding_transcript_exon_variant	Exon 1 of 11	2		ENSP00000435426.1	Q496Y0-3

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112435

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34591

show subpopulations

Gnomad AFR

AF:

0.0000645

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000473

AC:

AN:

169044

Hom.:

AF XY:

0.0000514

AC XY:

AN XY:

58402

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000376

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:

0.0000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000731

AC:

AN:

1094402

Hom.:

Cov.:

AF XY:

0.0000610

AC XY:

AN XY:

360672

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000287

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:

0.0000868

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112435

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34591

show subpopulations

Gnomad4 AFR

AF:

0.0000645

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 31, 2023

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. -

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LONRF3: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.84

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over