Genetic Variant LRRC25:p.Pro213Arg (chr19-18396326-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145256.3(LRRC25):c.638C>G(p.Pro213Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 0 hom. )

Consequence

LRRC25
NM_145256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.300

Variant links:

Genes affected

LRRC25 (HGNC:29806): (leucine rich repeat containing 25) Predicted to be located in cytoplasm. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.040493846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC25	NM_145256.3 link	c.638C>G	p.Pro213Arg	missense_variant	Exon 1 of 2	ENST00000339007.4	NP_660299.2	Q8N386
LRRC25	XM_005259739.5 link	c.638C>G	p.Pro213Arg	missense_variant	Exon 2 of 3		XP_005259796.1	Q8N386

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC25	ENST00000339007.4 link	c.638C>G	p.Pro213Arg	missense_variant	Exon 1 of 2	1	NM_145256.3	ENSP00000340983.2		Q8N386
LRRC25	ENST00000595840.1 link	c.638C>G	p.Pro213Arg	missense_variant	Exon 2 of 3	1		ENSP00000472290.1		Q8N386

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000705

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000416

AC:

104

AN:

250104

Hom.:

AF XY:

0.000384

AC XY:

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.000683

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000638

AC:

932

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000609

AC XY:

443

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000394

Gnomad4 NFE exome

AF:

0.000770

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000368

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000705

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000558

Hom.:

Bravo

AF:

0.000370

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000437

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.638C>G (p.P213R) alteration is located in exon 1 (coding exon 1) of the LRRC25 gene. This alteration results from a C to G substitution at nucleotide position 638, causing the proline (P) at amino acid position 213 to be replaced by an arginine (R). 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

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.48

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.040

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.2

D;.

REVEL

Benign

0.020

Sift

Uncertain

0.011

D;.

Sift4G

Uncertain

0.010

D;D

Polyphen

0.72

P;P

Vest4

0.11

MVP

0.068

MPC

0.60

ClinPred

0.12

GERP RS

1.8

Varity_R

0.095

gMVP

0.23

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