6-53896863-G-A

Position:

• chr6-53896863-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018214.5(LRRC1):​c.538G>A​(p.Asp180Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LRRC1 NM_018214.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

Genes affected

LRRC1 (HGNC:14307): (leucine rich repeat containing 1) Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC1	NM_018214.5	c.538G>A	p.Asp180Asn	missense_variant	6/14	ENST00000370888.6	NP_060684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC1	ENST00000370888.6	c.538G>A	p.Asp180Asn	missense_variant	6/14	1	NM_018214.5	ENSP00000359925	P1
LRRC1	ENST00000487251.5	c.538G>A	p.Asp180Asn	missense_variant, NMD_transcript_variant	7/11	2		ENSP00000435217

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451076 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722608

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Nov 10, 2022

The c.538G>A (p.D180N) alteration is located in exon 6 (coding exon 6) of the LRRC1 gene. This alteration results from a G to A substitution at nucleotide position 538, causing the aspartic acid (D) at amino acid position 180 to be replaced by an asparagine (N). 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	Pathogenic	0.98
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.076	T
Polyphen		1.0	D
Vest4		0.78
MutPred		0.54		Loss of solvent accessibility (P = 0.1279);
MVP		0.36
MPC		1.0
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.69

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: chr6-53761661;