10-48914136-C-A

Variant names:

• chr10-48914136-C-A
• rs7094610
• NM_001378102.1:c.20G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378102.1(LRRC18):​c.20G>T​(p.Gly7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,613,084 control chromosomes in the GnomAD database, including 99,512 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (7864 hom., cov: 33)
  • Exomes 𝑓: 0.34 (91648 hom.)
• Consequence: LRRC18 NM_001378102.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.169
• Publications: 29 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3019155E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

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.20G>T	p.Gly7Val	missense	Exon 3 of 4	NP_001365031.1	Q8N456-1
	WDFY4	NM_001394531.1	MANE Select	c.7586+12273C>A		intron	N/A	NP_001381460.1	Q6ZS81-1
	LRRC18	NM_001006939.4		c.20G>T	p.Gly7Val	missense	Exon 2 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.20G>T	p.Gly7Val	missense	Exon 3 of 4	ENSP00000363275.3	Q8N456-1
	WDFY4	ENST00000325239.12	TSL:5 MANE Select	c.7586+12273C>A		intron	N/A	ENSP00000320563.5	Q6ZS81-1
	WDFY4	ENST00000858472.1		c.7586+12273C>A		intron	N/A	ENSP00000528531.1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44609 AN: 151928 Hom.: 7866 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.347

GnomAD2 exomes AF: 0.358 AC: 89678 AN: 250498 AF XY: 0.366

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.377

Gnomad EAS exome AF: 0.719

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.344 AC: 502909 AN: 1461038 Hom.: 91648 Cov.: 40 AF XY: 0.347 AC XY: 252445 AN XY: 726798

African (AFR) AF: 0.0978 AC: 3272 AN: 33462

American (AMR) AF: 0.302 AC: 13482 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9808 AN: 26122

East Asian (EAS) AF: 0.740 AC: 29356 AN: 39688

South Asian (SAS) AF: 0.416 AC: 35847 AN: 86222

European-Finnish (FIN) AF: 0.337 AC: 17909 AN: 53190

Middle Eastern (MID) AF: 0.393 AC: 2250 AN: 5718

European-Non Finnish (NFE) AF: 0.332 AC: 369070 AN: 1111554

Other (OTH) AF: 0.363 AC: 21915 AN: 60370

GnomAD4 genome AF: 0.293 AC: 44595 AN: 152046 Hom.: 7864 Cov.: 33 AF XY: 0.301 AC XY: 22335 AN XY: 74304

African (AFR) AF: 0.109 AC: 4542 AN: 41518

American (AMR) AF: 0.329 AC: 5032 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1347 AN: 3466

East Asian (EAS) AF: 0.718 AC: 3693 AN: 5144

South Asian (SAS) AF: 0.439 AC: 2114 AN: 4816

European-Finnish (FIN) AF: 0.349 AC: 3691 AN: 10564

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22964 AN: 67948

Other (OTH) AF: 0.346 AC: 730 AN: 2110

Alfa AF: 0.335 Hom.: 39522

Bravo AF: 0.282

TwinsUK AF: 0.334 AC: 1237

ALSPAC AF: 0.331 AC: 1276

ESP6500AA AF: 0.113 AC: 499

ESP6500EA AF: 0.346 AC: 2973

ExAC AF: 0.354 AC: 42940

Asia WGS AF: 0.521 AC: 1815 AN: 3478

EpiCase AF: 0.351

EpiControl AF: 0.348

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.69
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.17
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.055
Sift	Benign	0.28	T
Sift4G	Benign	0.23	T
Polyphen		0.034	B
Vest4		0.075
MPC		0.017
ClinPred		0.0041	T
GERP RS		0.75
PromoterAI		-0.037	Neutral
Varity_R		0.084
gMVP		0.47
Mutation Taster		=95/5	polymorphism (auto)

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: rs7094610; hg19: chr10-50122181; COSMIC: COSV53282836;