20-36198013-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012156.2(EPB41L1):c.1640C>G(p.Pro547Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,613,664 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 61 hom. )

Consequence

EPB41L1
NM_012156.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.43

Publications

10 publications found

Variant links:

Genes affected

EPB41L1 (HGNC:3378): (erythrocyte membrane protein band 4.1 like 1) Erythrocyte membrane protein band 4.1 (EPB41) is a multifunctional protein that mediates interactions between the erythrocyte cytoskeleton and the overlying plasma membrane. The encoded protein binds and stabilizes D2 and D3 dopamine receptors at the neuronal plasma membrane. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

EPB41L1 Gene-Disease associations (from GenCC):

autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
intellectual disability, autosomal dominant 11
Inheritance: AD Classification: LIMITED Submitted by: G2P

EPB41L1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005582273).

BP6

Variant 20-36198013-C-G is Benign according to our data. Variant chr20-36198013-C-G is described in ClinVar as Benign. ClinVar VariationId is 128997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00698 (10202/1461444) while in subpopulation SAS AF = 0.017 (1464/86254). AF 95% confidence interval is 0.0162. There are 61 homozygotes in GnomAdExome4. There are 5308 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.

BS2

High AC in GnomAd4 at 784 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41L1	NM_012156.2 link	c.1640C>G	p.Pro547Arg	missense_variant	Exon 14 of 22	ENST00000338074.7	NP_036288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41L1	ENST00000338074.7 link	c.1640C>G	p.Pro547Arg	missense_variant	Exon 14 of 22	1	NM_012156.2	ENSP00000337168.2

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

784

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0164

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00712

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00718

AC:

1785

AN:

248490

AF XY:

0.00805

show subpopulations

Gnomad AFR exome

AF:

0.00121

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00569

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00519

Gnomad NFE exome

AF:

0.00847

Gnomad OTH exome

AF:

0.00576

GnomAD4 exome

AF:

0.00698

AC:

10202

AN:

1461444

Hom.:

Cov.:

AF XY:

0.00730

AC XY:

5308

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33472

American (AMR)

AF:

0.00255

AC:

114

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00532

AC:

139

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0170

AC:

1464

AN:

86254

European-Finnish (FIN)

AF:

0.00592

AC:

314

AN:

53062

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00693

AC:

7710

AN:

1111970

Other (OTH)

AF:

0.00623

AC:

376

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

640

1280

1920

2560

3200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

288

576

864

1152

1440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00515

AC:

784

AN:

152220

Hom.:

Cov.:

AF XY:

0.00495

AC XY:

368

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41538

American (AMR)

AF:

0.00503

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.0164

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00712

AC:

484

AN:

68004

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00327

Hom.:

Bravo

AF:

0.00488

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00804

AC:

976

EpiCase

AF:

0.00742

EpiControl

AF:

0.00771

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Nov 02, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;.;.;.;.;T;.;T

Eigen

Benign

0.059

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;D;D;D;D;.;D

MetaRNN

Benign

0.0056

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.070

MutationAssessor

Benign

0.69

.;.;.;.;.;N;.;.

PhyloP100

7.4

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.3

N;D;N;.;.;N;D;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.018

D;D;D;.;.;D;D;D

Sift4G

Uncertain

0.030

D;D;D;D;T;D;D;T

Polyphen

0.0090

B;D;B;.;P;D;.;.

Vest4

0.47

MVP

0.58

MPC

0.83

ClinPred

0.030

GERP RS

5.2

PromoterAI

-0.0074

Neutral

(source)

Varity_R

0.16

gMVP

0.41

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over