18-5397297-C-T

Variant names:

• chr18-5397297-C-T
• rs148568579
• NM_012307.5:c.2602G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012307.5(EPB41L3):​c.2602G>A​(p.Gly868Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: EPB41L3 NM_012307.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.08317876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41L3	NM_012307.5	c.2602G>A	p.Gly868Arg	missense_variant	Exon 18 of 23	ENST00000341928.7	NP_036439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41L3	ENST00000341928.7	c.2602G>A	p.Gly868Arg	missense_variant	Exon 18 of 23	1	NM_012307.5	ENSP00000343158.2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251264 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727208

Gnomad4 AFR exome AF: 0.000687 AC: 23 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53314

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1112008

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74456

Gnomad4 AFR AF: 0.000553 AC: 0.00055347 AN: 0.00055347

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000194 AC: 0.000193949 AN: 0.000193949

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000375 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2602G>A (p.G868R) alteration is located in exon 18 (coding exon 17) of the EPB41L3 gene. This alteration results from a G to A substitution at nucleotide position 2602, causing the glycine (G) at amino acid position 868 to be replaced by an arginine (R). 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	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.11	.;.;T;.;.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.083	T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.4	.;.;M;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.90	N;.;N;.;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.15	T;.;T;.;.;.;.
Sift4G	Benign	0.45	T;T;T;.;T;T;.
Polyphen		0.092, 0.71, 0.13	.;.;B;.;P;B;.
Vest4		0.34
MutPred		0.33		.;.;Gain of solvent accessibility (P = 0.0037);.;.;.;.;
MVP		0.76
MPC		0.21
ClinPred		0.12	T
GERP RS		5.7
Varity_R		0.12
gMVP		0.27
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs148568579; hg19: chr18-5397296;