8-91200731-T-C

Position:

• chr8-91200731-T-C

Variant summary

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

The NM_001129890.2(LRRC69):​c.872T>C​(p.Ile291Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 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)
• Consequence: LRRC69 NM_001129890.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

Genes affected

LRRC69 (HGNC:34303): (leucine rich repeat containing 69) Predicted to be involved in signal transduction. [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=0.31695563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC69	NM_001129890.2	c.872T>C	p.Ile291Thr	missense_variant	7/8	ENST00000448384.3	NP_001123362.1
LRRC69	NM_001354470.2	c.404T>C	p.Ile135Thr	missense_variant	3/4		NP_001341399.1
LRRC69	NR_148895.2	n.1314T>C		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC69	ENST00000448384.3	c.872T>C	p.Ile291Thr	missense_variant	7/8	5	NM_001129890.2	ENSP00000400803	P1
LRRC69	ENST00000343709.7	c.404T>C	p.Ile135Thr	missense_variant	3/4	2		ENSP00000343221
LRRC69	ENST00000520099.5	c.*1061T>C		3_prime_UTR_variant, NMD_transcript_variant	9/11	2		ENSP00000428537

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000684 AC: 1 AN: 146220 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 77240

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: 0.0000171

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000388 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

May 31, 2024

The c.872T>C (p.I291T) alteration is located in exon 7 (coding exon 7) of the LRRC69 gene. This alteration results from a T to C substitution at nucleotide position 872, causing the isoleucine (I) at amino acid position 291 to be replaced by a threonine (T). 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	0.21
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	.;M
MutationTaster	Benign	0.79	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.94	P;B
Vest4		0.76
MutPred		0.47		.;Loss of sheet (P = 0.003);
MVP		0.13
ClinPred		0.19	T
GERP RS		4.1
Varity_R		0.065
gMVP		0.065

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

Other links and lift over

dbSNP: rs755162764; hg19: chr8-92212959;