18-5397324-C-G

Position:

• chr18-5397324-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012307.5(EPB41L3):​c.2575G>C​(p.Glu859Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00139 in 1,614,070 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0073 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (14 hom.)
• Consequence: EPB41L3 NM_012307.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.70

Genes affected

EPB41L3 (HGNC:3380): (erythrocyte membrane protein band 4.1 like 3) Predicted to enable cytoskeletal protein-membrane anchor activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in several processes, including nervous system development; paranodal junction maintenance; and protein localization to paranode region of axon. Located in cell-cell junction and plasma membrane. Biomarker of meningioma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057339966).
• BP6: Variant 18-5397324-C-G is Benign according to our data. Variant chr18-5397324-C-G is described in ClinVar as [Benign]. Clinvar id is 777266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0073 (1112/152330) while in subpopulation AFR AF= 0.0252 (1048/41570). AF 95% confidence interval is 0.0239. There are 15 homozygotes in gnomad4. There are 560 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB41L3	NM_012307.5	c.2575G>C	p.Glu859Gln	missense_variant	18/23	ENST00000341928.7	NP_036439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB41L3	ENST00000341928.7	c.2575G>C	p.Glu859Gln	missense_variant	18/23	1	NM_012307.5	ENSP00000343158.2

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1115 AN: 152212 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00187 AC: 470 AN: 251152 Hom.: 6 AF XY: 0.00137 AC XY: 186 AN XY: 135774

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000777 AC: 1136 AN: 1461740 Hom.: 14 Cov.: 31 AF XY: 0.000690 AC XY: 502 AN XY: 727198

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00730 AC: 1112 AN: 152330 Hom.: 15 Cov.: 32 AF XY: 0.00752 AC XY: 560 AN XY: 74484

Gnomad4 AFR AF: 0.0252

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00113 Hom.: 1

Bravo AF: 0.00819

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00231 AC: 281

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;.;T;.;.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D
MetaRNN	Benign	0.0057	T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	.;.;M;.;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.83	N;.;N;.;.;.;.
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;.;D;.;.;.;.
Sift4G	Benign	0.42	T;T;T;.;T;T;.
Polyphen		0.99, 0.99, 0.79	.;.;D;.;D;P;.
Vest4		0.42
MVP		0.70
MPC		0.18
ClinPred		0.069	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.33

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: rs8096452; hg19: chr18-5397323;