1-100158232-T-G

Position:

• chr1-100158232-T-G

Variant summary

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

The NM_144620.4(LRRC39):​c.512A>C​(p.Glu171Ala) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRC39 NM_144620.4 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75

Genes affected

LRRC39 (HGNC:28228): (leucine rich repeat containing 39) Predicted to enable protein serine/threonine phosphatase activity. Predicted to be involved in signal transduction. Predicted to be located in M band. Predicted to be active in cytoplasm and intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC39	NM_144620.4	c.512A>C	p.Glu171Ala	missense_variant, splice_region_variant	6/10	ENST00000370137.6	NP_653221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC39	ENST00000370137.6	c.512A>C	p.Glu171Ala	missense_variant, splice_region_variant	6/10	1	NM_144620.4	ENSP00000359156	P1
LRRC39	ENST00000370138.1	c.512A>C	p.Glu171Ala	missense_variant, splice_region_variant	6/11	5		ENSP00000359157
LRRC39	ENST00000342895.8	c.512A>C	p.Glu171Ala	missense_variant, splice_region_variant	6/10	5		ENSP00000344470	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 31, 2023

The c.512A>C (p.E171A) alteration is located in exon 6 (coding exon 4) of the LRRC39 gene. This alteration results from a A to C substitution at nucleotide position 512, causing the glutamic acid (E) at amino acid position 171 to be replaced by an alanine (A). 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	0.15
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.0	.;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.010	.;D;D;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.79	P;P;P;P
Vest4		0.26
MutPred		0.45		Gain of catalytic residue at E171 (P = 0.1411);Gain of catalytic residue at E171 (P = 0.1411);Gain of catalytic residue at E171 (P = 0.1411);Gain of catalytic residue at E171 (P = 0.1411);
MVP		0.46
MPC		0.13
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.31
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.11		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: chr1-100623788;