18-5397405-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012307.5(EPB41L3):c.2494T>G(p.Ser832Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,620 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (7 hom.)
• Consequence: EPB41L3 NM_012307.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0810

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031062663).
• BP6: Variant 18-5397405-A-C is Benign according to our data. Variant chr18-5397405-A-C is described in ClinVar as [Benign]. Clinvar id is 788000.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00553 (840/151868) while in subpopulation AFR AF= 0.0186 (772/41416). AF 95% confidence interval is 0.0175. There are 7 homozygotes in gnomad4. There are 395 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB41L3	NM_012307.5	c.2494T>G	p.Ser832Ala	missense_variant	18/23	ENST00000341928.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB41L3	ENST00000341928.7	c.2494T>G	p.Ser832Ala	missense_variant	18/23	1	NM_012307.5

Frequencies

GnomAD3 genomes AF: 0.00554 AC: 840 AN: 151750 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00250

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00155 AC: 386 AN: 249088 Hom.: 5 AF XY: 0.00125 AC XY: 168 AN XY: 134596

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.000613

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000280

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000615 AC: 897 AN: 1458752 Hom.: 7 Cov.: 31 AF XY: 0.000589 AC XY: 427 AN XY: 725356

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.000899

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00553 AC: 840 AN: 151868 Hom.: 7 Cov.: 33 AF XY: 0.00532 AC XY: 395 AN XY: 74188

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000951

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00144 Hom.: 2

Bravo AF: 0.00587

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0193 AC: 85

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00209 AC: 254

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000416

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	10
Dann	Benign	0.92
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N;.;N;.;.;.;.;.;.
REVEL	Benign	0.15
Sift	Uncertain	0.025	D;.;D;.;.;.;.;.;.
Sift4G	Benign	0.48	T;T;T;.;T;T;.;.;.
Polyphen		0.0010, 0.023, 0.044	.;.;B;.;B;B;.;.;.
Vest4		0.33
MVP		0.56
MPC		0.14
ClinPred		0.0042	T
GERP RS		-4.7
Varity_R		0.048
gMVP		0.10

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: rs116459026; hg19: chr18-5397404; COSMIC: COSV99048678; COSMIC: COSV99048678;