19-18396338-T-C

Variant names:

• chr19-18396338-T-C
• NM_145256.3:c.626A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145256.3(LRRC25):​c.626A>G​(p.Asp209Gly) 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 1,461,526 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRRC25 NM_145256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00400

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13307554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC25	NM_145256.3	c.626A>G	p.Asp209Gly	missense_variant	Exon 1 of 2	ENST00000339007.4	NP_660299.2
LRRC25	XM_005259739.5	c.626A>G	p.Asp209Gly	missense_variant	Exon 2 of 3		XP_005259796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC25	ENST00000339007.4	c.626A>G	p.Asp209Gly	missense_variant	Exon 1 of 2	1	NM_145256.3	ENSP00000340983.2
LRRC25	ENST00000595840.1	c.626A>G	p.Asp209Gly	missense_variant	Exon 2 of 3	1		ENSP00000472290.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461526 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727088

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

Aug 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.626A>G (p.D209G) alteration is located in exon 1 (coding exon 1) of the LRRC25 gene. This alteration results from a A to G substitution at nucleotide position 626, causing the aspartic acid (D) at amino acid position 209 to be replaced by a glycine (G). 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	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.2
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.51	.;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Benign	0.036
Sift	Uncertain	0.015	D;.
Sift4G	Uncertain	0.058	T;T
Polyphen		0.89	P;P
Vest4		0.074
MutPred		0.29		Loss of ubiquitination at K212 (P = 0.0184);Loss of ubiquitination at K212 (P = 0.0184);
MVP		0.20
MPC		0.69
ClinPred		0.55	D
GERP RS		3.0
Varity_R		0.28
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18507148;