19-18396308-G-A

Position:

• chr19-18396308-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000339007.4(LRRC25):​c.656C>T​(p.Pro219Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRRC25 ENST00000339007.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30669093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC25	NM_145256.3	c.656C>T	p.Pro219Leu	missense_variant	1/2	ENST00000339007.4	NP_660299.2
LRRC25	XM_005259739.5	c.656C>T	p.Pro219Leu	missense_variant	2/3		XP_005259796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC25	ENST00000339007.4	c.656C>T	p.Pro219Leu	missense_variant	1/2	1	NM_145256.3	ENSP00000340983.2
LRRC25	ENST00000595840.1	c.656C>T	p.Pro219Leu	missense_variant	2/3	1		ENSP00000472290.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461512 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2024

The c.656C>T (p.P219L) alteration is located in exon 1 (coding exon 1) of the LRRC25 gene. This alteration results from a C to T substitution at nucleotide position 656, causing the proline (P) at amino acid position 219 to be replaced by a leucine (L). 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	0.17
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	0.022
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.6	D;.
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.25
MutPred		0.43		Gain of MoRF binding (P = 0.0528);Gain of MoRF binding (P = 0.0528);
MVP		0.25
MPC		1.3
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.55
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-18507118;