3-169848248-T-C

Variant summary

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

The NM_024727.4(LRRC31):c.1199A>G(p.Asn400Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRRC31 NM_024727.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

Genes affected

LRRC31 (HGNC:26261): (leucine rich repeat containing 31)

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=0.26248914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC31	NM_024727.4	c.1199A>G	p.Asn400Ser	missense_variant	8/9	ENST00000316428.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC31	ENST00000316428.10	c.1199A>G	p.Asn400Ser	missense_variant	8/9	1	NM_024727.4	P1
LRRC31	ENST00000523069.1	c.1199A>G	p.Asn400Ser	missense_variant	8/9	1
LRRC31	ENST00000264676.9	c.1031A>G	p.Asn344Ser	missense_variant	7/8	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249504 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135356

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

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

Mar 17, 2023

The c.1199A>G (p.N400S) alteration is located in exon 9 (coding exon 8) of the LRRC31 gene. This alteration results from a A to G substitution at nucleotide position 1199, causing the asparagine (N) at amino acid position 400 to be replaced by a serine (S). 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	0.051
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	6.1
Dann	Benign	0.51
DEOGEN2	Benign	0.014	T;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.069
Sift	Uncertain	0.022	D;D;D
Sift4G	Benign	0.18	T;D;T
Polyphen		0.0060	B;B;.
Vest4		0.16
MutPred		0.61		Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);
MVP		0.46
MPC		0.027
ClinPred		0.064	T
GERP RS		0.92
Varity_R		0.086
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs753633165; hg19: chr3-169566036;