Genetic Variant EPB41L1:p.Phe242Phe (chr20-36185276-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_012156.2(EPB41L1):c.726C>T(p.Phe242Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,613,824 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 13 hom. )

Consequence

EPB41L1
NM_012156.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.48

Publications

1 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:

LOC124904892 (HGNC:):

LOC124904892 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 20-36185276-C-T is Benign according to our data. Variant chr20-36185276-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.48 with no splicing effect.

BS2

High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41L1	NM_012156.2 link	c.726C>T	p.Phe242Phe	synonymous_variant	Exon 7 of 22	ENST00000338074.7	NP_036288.2	Q9H4G0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41L1	ENST00000338074.7 link	c.726C>T	p.Phe242Phe	synonymous_variant	Exon 7 of 22	1	NM_012156.2	ENSP00000337168.2		Q9H4G0-1

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

248

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00269

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00154

AC:

386

AN:

250810

AF XY:

0.00167

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.00259

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00261

AC:

3816

AN:

1461508

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1883

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33472

American (AMR)

AF:

0.000291

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00218

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00161

AC:

139

AN:

86242

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53246

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.00311

AC:

3463

AN:

1112008

Other (OTH)

AF:

0.00194

AC:

117

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

237

474

712

949

1186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00163

AC:

248

AN:

152316

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41564

American (AMR)

AF:

0.000327

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00269

AC:

183

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00237

Hom.:

Bravo

AF:

0.00178

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00261

ClinVar

Significance: Benign/Likely 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Feb 20, 2017

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

BayesDel_noAF

Benign

-0.33

CADD

Benign

6.6

(source)

DANN

Benign

0.65

PhyloP100

-1.5

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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