1-53962061-T-C

Position:

• chr1-53962061-T-C

Variant summary

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

The NM_001256409.2(LRRC42):​c.752T>C​(p.Ile251Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,622 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: 6.8e-7 (0 hom.)
• Consequence: LRRC42 NM_001256409.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71

Genes affected

LRRC42 (HGNC:28792): (leucine rich repeat containing 42)

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, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC42	NM_001256409.2	c.752T>C	p.Ile251Thr	missense_variant	6/9	ENST00000371370.8	NP_001243338.1
LRRC42	NM_052940.5	c.752T>C	p.Ile251Thr	missense_variant	5/8		NP_443172.1
LRRC42	XM_006710328.5	c.752T>C	p.Ile251Thr	missense_variant	6/9		XP_006710391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC42	ENST00000371370.8	c.752T>C	p.Ile251Thr	missense_variant	6/9	2	NM_001256409.2	ENSP00000360421	P1
LRRC42	ENST00000319223.8	c.752T>C	p.Ile251Thr	missense_variant	5/8	1		ENSP00000318185	P1
LRRC42	ENST00000713564.1	c.752T>C	p.Ile251Thr	missense_variant	6/9			ENSP00000518857	P1
LRRC42	ENST00000477905.1	n.109T>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461622 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727120

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.752T>C (p.I251T) alteration is located in exon 5 (coding exon 4) of the LRRC42 gene. This alteration results from a T to C substitution at nucleotide position 752, causing the isoleucine (I) at amino acid position 251 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	Uncertain	0.34
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.97	D;D
Vest4		0.91
MutPred		0.68		Loss of stability (P = 0.0774);Loss of stability (P = 0.0774);
MVP		0.47
MPC		0.36
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.28
gMVP		0.45

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: rs1655008211; hg19: chr1-54427734;