Genetic Variant NM_001031855.3:c.613G>A (chrX-118975393-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001031855.3(LONRF3):c.613G>A(p.Ala205Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,202,208 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.0000037 ( 0 hom. 0 hem. )

Consequence

LONRF3
NM_001031855.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.754

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07969257).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031855.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LONRF3	NM_001031855.3	MANE Select	c.613G>A	p.Ala205Thr	missense	Exon 1 of 11	NP_001027026.1	Q496Y0-1
LONRF3	NM_024778.5		c.613G>A	p.Ala205Thr	missense	Exon 1 of 10	NP_079054.3	A8K2D3
LONRF3	NR_110311.1		n.780G>A		non_coding_transcript_exon	Exon 1 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LONRF3	ENST00000371628.8	TSL:1 MANE Select	c.613G>A	p.Ala205Thr	missense	Exon 1 of 11	ENSP00000360690.3	Q496Y0-1
LONRF3	ENST00000304778.11	TSL:1	c.613G>A	p.Ala205Thr	missense	Exon 1 of 10	ENSP00000307732.7	Q496Y0-2
LONRF3	ENST00000439603.6	TSL:1	c.31G>A	p.Ala11Thr	missense	Exon 1 of 10	ENSP00000414519.1	H0Y7Q8

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112971

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000564

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

GnomAD2 exomes

AF:

0.0000456

AC:

AN:

153586

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000574

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000367

AC:

AN:

1089237

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357149

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26026

American (AMR)

AF:

0.00

AC:

AN:

34470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19153

East Asian (EAS)

AF:

0.000101

AC:

AN:

29790

South Asian (SAS)

AF:

0.00

AC:

AN:

53114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38815

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

838176

Other (OTH)

AF:

0.00

AC:

AN:

45649

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112971

Hom.:

Cov.:

AF XY:

0.0000569

AC XY:

AN XY:

35143

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31159

American (AMR)

AF:

0.00

AC:

AN:

10873

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.000564

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53264

Other (OTH)

AF:

0.00

AC:

AN:

1522

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000508

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.032

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.080

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.75

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.79

REVEL

Benign

0.13

Sift

Benign

0.22

Sift4G

Benign

0.17

Polyphen

0.0030

Vest4

0.066

MutPred

0.27

Gain of glycosylation at A205 (P = 0.0698)

MVP

0.67

MPC

0.37

ClinPred

0.027

GERP RS

-1.8

PromoterAI

-0.10

Neutral

(source)

Varity_R

0.069

gMVP

0.28

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over