dbSNP rs6089016: EPB41L1:p.Pro547His (chr20-36198013-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_012156.2(EPB41L1):c.1640C>A(p.Pro547His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P547R) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EPB41L1
NM_012156.2 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37107116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41L1	NM_012156.2 link	c.1640C>A	p.Pro547His	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>A	p.Pro547His	missense_variant	Exon 14 of 22	1	NM_012156.2	ENSP00000337168.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248490

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461446

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727022

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111972

Other (OTH)

AF:

0.0000166

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

.;.;.;.;.;D;.;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.049

MetaRNN

Benign

0.37

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

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.69

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

PhyloP100

7.4

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.4

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

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.017

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

Polyphen

0.047

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

Vest4

0.46

MutPred

0.24

.;.;.;Gain of loop (P = 0.0013);.;Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);.;

MVP

0.64

MPC

0.43

ClinPred

0.89

GERP RS

5.2

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.42

gMVP

0.35

Mutation Taster

=79/21

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over