NM_001378102.1:c.770G>A

Variant names:

• chr10-48910253-C-T
• rs764699947
• NM_001378102.1:c.770G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001378102.1(LRRC18):​c.770G>A​(p.Arg257His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,612,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: LRRC18 NM_001378102.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.362
• Publications: 0 publications found

Genes affected

LRRC18 (HGNC:23199): (leucine rich repeat containing 18) Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

WDFY4 (HGNC:29323): (WDFY family member 4) Predicted to be involved in autophagy. Predicted to act upstream of or within with a positive effect on CD8-positive, alpha-beta T cell activation. Predicted to act upstream of or within antigen processing and presentation and cellular response to virus. Predicted to be located in early endosome and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

WDFY4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000241577 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0618625).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378102.1. 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
	LRRC18	NM_001378102.1	MANE Select	c.770G>A	p.Arg257His	missense	Exon 4 of 4	NP_001365031.1	Q8N456-1
	WDFY4	NM_001394531.1	MANE Select	c.7586+8390C>T		intron	N/A	NP_001381460.1	Q6ZS81-1
	LRRC18	NM_001006939.4		c.770G>A	p.Arg257His	missense	Exon 3 of 3	NP_001006940.3	Q8N456-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC18	ENST00000374160.8	TSL:1 MANE Select	c.770G>A	p.Arg257His	missense	Exon 4 of 4	ENSP00000363275.3	Q8N456-1
	WDFY4	ENST00000325239.12	TSL:5 MANE Select	c.7586+8390C>T		intron	N/A	ENSP00000320563.5	Q6ZS81-1
	WDFY4	ENST00000858472.1		c.7586+8390C>T		intron	N/A	ENSP00000528531.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151998 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251262 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1460116 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 726410

African (AFR) AF: 0.0000299 AC: 1 AN: 33416

American (AMR) AF: 0.0000448 AC: 2 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.0000938 AC: 5 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1110792

Other (OTH) AF: 0.0000166 AC: 1 AN: 60298

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151998 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74236

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	0.078
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.46
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.36
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.060
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.19
MPC		0.035
ClinPred		0.15	T
GERP RS		-5.8
Varity_R		0.049
gMVP		0.47
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs764699947; hg19: chr10-50118298; COSMIC: COSV99630821;