rs548519774

Variant names:

• chr7-100575996-G-A
• rs548519774
• NM_002319.5:c.1651C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002319.5(LRCH4):​c.1651C>T​(p.Arg551Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000237 in 1,604,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R551Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: LRCH4 NM_002319.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• Publications: 0 publications found

Genes affected

LRCH4 (HGNC:6691): (leucine rich repeats and calponin homology domain containing 4) This gene encodes a protein that contains leucine-rich repeats (LRR) at its amino terminus and that is known to be involved in ligand binding. The carboxyl terminus may act as a membrane anchor. Identified structural elements suggest that the encoded protein resembles a receptor. [provided by RefSeq, Jul 2008]

ENSG00000274272 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002319.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRCH4	NM_002319.5	MANE Select	c.1651C>T	p.Arg551Trp	missense	Exon 16 of 18	NP_002310.2
	LRCH4	NM_001289934.2		c.1651C>T	p.Arg551Trp	missense	Exon 16 of 18	NP_001276863.1	H7C5D9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRCH4	ENST00000310300.11	TSL:1 MANE Select	c.1651C>T	p.Arg551Trp	missense	Exon 16 of 18	ENSP00000309689.6	O75427
	LRCH4	ENST00000877649.1		c.1663C>T	p.Arg555Trp	missense	Exon 16 of 18	ENSP00000547708.1
	LRCH4	ENST00000965051.1		c.1648C>T	p.Arg550Trp	missense	Exon 16 of 18	ENSP00000635110.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000342 AC: 8 AN: 233678 AF XY: 0.0000313

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000374

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.0000220 AC: 32 AN: 1452400 Hom.: 0 Cov.: 33 AF XY: 0.0000208 AC XY: 15 AN XY: 722546

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1110732

Other (OTH) AF: 0.0000332 AC: 2 AN: 60184

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74496

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000727 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.6
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.53		Loss of disorder (P = 0.0067)
MVP		0.96
MPC		0.43
ClinPred		0.74	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.66
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs548519774; hg19: chr7-100173619;