Genetic Variant EPB41L5:p.Thr53Ala (chr2-120019241-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020909.4(EPB41L5):c.157A>G(p.Thr53Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000023 in 1,611,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

EPB41L5
NM_020909.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.78

Publications

0 publications found

Variant links:

Genes affected

EPB41L5 (HGNC:19819): (erythrocyte membrane protein band 4.1 like 5) Predicted to enable cytoskeletal protein binding activity and protein domain specific binding activity. Predicted to be involved in actomyosin structure organization. Predicted to act upstream of or within several processes, including chordate embryonic development; embryonic foregut morphogenesis; and mesoderm morphogenesis. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

EPB41L5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41L5	NM_020909.4 link	c.157A>G	p.Thr53Ala	missense_variant	Exon 2 of 25	ENST00000263713.10	NP_065960.2	Q9HCM4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41L5	ENST00000263713.10 link	c.157A>G	p.Thr53Ala	missense_variant	Exon 2 of 25	1	NM_020909.4	ENSP00000263713.5		Q9HCM4-1

Frequencies

GnomAD3 genomes

AF:

0.0000856

AC:

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000948

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000401

AC:

AN:

249068

AF XY:

0.0000297

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1460064

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33288

American (AMR)

AF:

0.00

AC:

AN:

43922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86116

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111594

Other (OTH)

AF:

0.0000498

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000856

AC:

AN:

151926

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74158

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41344

American (AMR)

AF:

0.00

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000948

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.157A>G (p.T53A) alteration is located in exon 2 (coding exon 1) of the EPB41L5 gene. This alteration results from a A to G substitution at nucleotide position 157, causing the threonine (T) at amino acid position 53 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;.;.;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

T;T;.;T;T

M_CAP

Benign

0.082

MetaRNN

Uncertain

0.49

T;T;T;T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.1

M;M;M;M;M

PhyloP100

6.8

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.7

D;D;D;D;D

REVEL

Uncertain

0.63

Sift

Benign

0.077

T;T;T;T;T

Sift4G

Benign

0.074

T;T;T;T;T

Polyphen

0.99

D;D;B;B;.

Vest4

0.73

MutPred

0.63

Loss of stability (P = 0.1547);Loss of stability (P = 0.1547);Loss of stability (P = 0.1547);Loss of stability (P = 0.1547);Loss of stability (P = 0.1547);

MVP

0.73

MPC

0.43

ClinPred

0.66

GERP RS

5.0

PromoterAI

0.036

Neutral

(source)

Varity_R

0.21

gMVP

0.58

Mutation Taster

=35/65

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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2-120019241-A-G

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