18-5397065-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012307.5(EPB41L3):c.2834A>G(p.His945Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPB41L3 NM_012307.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15766922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB41L3	NM_012307.5	c.2834A>G	p.His945Arg	missense_variant	18/23	ENST00000341928.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB41L3	ENST00000341928.7	c.2834A>G	p.His945Arg	missense_variant	18/23	1	NM_012307.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.2834A>G (p.H945R) alteration is located in exon 18 (coding exon 17) of the EPB41L3 gene. This alteration results from a A to G substitution at nucleotide position 2834, causing the histidine (H) at amino acid position 945 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	0.075
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Benign	0.94
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.96	D;D;N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.2	N;.;N;.;.;.
REVEL	Benign	0.036
Sift	Uncertain	0.026	D;.;T;.;.;.
Sift4G	Benign	0.53	T;T;T;.;T;T
Polyphen		0.0	.;.;B;.;B;B
Vest4		0.32
MutPred		0.14		.;.;Gain of phosphorylation at S948 (P = 0.0689);.;.;.;
MVP		0.53
MPC		0.25
ClinPred		0.36	T
GERP RS		4.5
Varity_R		0.089
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-5397064;