18-5397129-G-A

Variant names:

• chr18-5397129-G-A
• rs146075320
• NM_012307.5:c.2770C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012307.5(EPB41L3):​c.2770C>T​(p.Arg924Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,114 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (8 hom.)
• Consequence: EPB41L3 NM_012307.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.88

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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002898723).
• BP6: Variant 18-5397129-G-A is Benign according to our data. Variant chr18-5397129-G-A is described in ClinVar as [Benign]. Clinvar id is 787999.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 = 0.00597 (909/152322) while in subpopulation AFR AF = 0.0202 (840/41560). AF 95% confidence interval is 0.0191. There are 9 homozygotes in GnomAd4. There are 428 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41L3	NM_012307.5	c.2770C>T	p.Arg924Cys	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.2770C>T	p.Arg924Cys	missense_variant	Exon 18 of 23	1	NM_012307.5	ENSP00000343158.2

Frequencies

GnomAD3 genomes AF: 0.00597 AC: 909 AN: 152204 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00168 AC: 422 AN: 251310 AF XY: 0.00132

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000663 AC: 969 AN: 1461792 Hom.: 8 Cov.: 31 AF XY: 0.000628 AC XY: 457 AN XY: 727194

Gnomad4 AFR exome AF: 0.0203 AC: 681 AN: 33480

Gnomad4 AMR exome AF: 0.000939 AC: 42 AN: 44710

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26128

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

Gnomad4 SAS exome AF: 0.0000232 AC: 2 AN: 86246

Gnomad4 FIN exome AF: 0.000131 AC: 7 AN: 53396

Gnomad4 NFE exome AF: 0.000138 AC: 153 AN: 1111972

Gnomad4 Remaining exome AF: 0.00131 AC: 79 AN: 60394

GnomAD4 genome AF: 0.00597 AC: 909 AN: 152322 Hom.: 9 Cov.: 32 AF XY: 0.00575 AC XY: 428 AN XY: 74478

Gnomad4 AFR AF: 0.0202 AC: 0.0202117 AN: 0.0202117

Gnomad4 AMR AF: 0.00255 AC: 0.00254835 AN: 0.00254835

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000941 AC: 0.0000941442 AN: 0.0000941442

Gnomad4 NFE AF: 0.000235 AC: 0.000235149 AN: 0.000235149

Gnomad4 OTH AF: 0.00614 AC: 0.00614367 AN: 0.00614367

Alfa AF: 0.00245 Hom.: 7

Bravo AF: 0.00637

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00219 AC: 266

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.12	.;.;T;.;.;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
MetaRNN	Benign	0.0029	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;.;N;.;.;.
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-1.0	N;.;N;.;.;.
REVEL	Benign	0.046
Sift	Uncertain	0.017	D;.;T;.;.;.
Sift4G	Benign	0.064	T;T;T;.;T;T
Polyphen		0.0, 0.0010	.;.;B;.;B;B
Vest4		0.14
MVP		0.52
MPC		0.22
ClinPred		0.025	T
GERP RS		4.1
Varity_R		0.071
gMVP		0.30
Mutation Taster		=93/7	polymorphism

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: rs146075320; hg19: chr18-5397128; COSMIC: COSV99048676; COSMIC: COSV99048676;