Genetic Variant EPB41L4A:p.Ala666Val (chr5-112165054-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_022140.5(EPB41L4A):c.1997C>T(p.Ala666Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000598 in 1,613,886 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00035 ( 1 hom. )

Consequence

EPB41L4A
NM_022140.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.93

Publications

2 publications found

Variant links:

Genes affected

EPB41L4A (HGNC:13278): (erythrocyte membrane protein band 4.1 like 4A) The protein encoded by this gene is a member of the band 4.1 protein superfamily. Members of this superfamily are thought to play an important role in regulating interactions between the cytoskeleton and plasma membrane, and contain an amino terminal conserved domain that binds glycophorin C. This gene product is thought to be involved in the beta-catenin signaling pathway. [provided by RefSeq, Dec 2016]

EPB41L4A links:

EPB41L4A-AS1 (HGNC:30749): (EPB41L4A antisense RNA 1)

EPB41L4A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050605834).

BP6

Variant 5-112165054-G-A is Benign according to our data. Variant chr5-112165054-G-A is described in ClinVar as Benign. ClinVar VariationId is 773173.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022140.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPB41L4A	NM_022140.5	MANE Select	c.1997C>T	p.Ala666Val	missense	Exon 23 of 23	NP_071423.4
EPB41L4A	NM_001347887.2		c.1932+3685C>T		intron	N/A	NP_001334816.1
EPB41L4A	NR_144931.2		n.2280C>T		non_coding_transcript_exon	Exon 23 of 23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPB41L4A	ENST00000261486.6	TSL:1 MANE Select	c.1997C>T	p.Ala666Val	missense	Exon 23 of 23	ENSP00000261486.5	Q9HCS5
EPB41L4A	ENST00000509342.6	TSL:5	n.445C>T		non_coding_transcript_exon	Exon 6 of 6
EPB41L4A	ENST00000507810.5	TSL:2	n.952+3685C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

460

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000797

AC:

198

AN:

248568

AF XY:

0.000608

show subpopulations

Gnomad AFR exome

AF:

0.00982

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000346

AC:

506

AN:

1461688

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

226

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.0105

AC:

350

AN:

33472

American (AMR)

AF:

0.00123

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111858

Other (OTH)

AF:

0.000960

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00302

AC:

459

AN:

152198

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0104

AC:

431

AN:

41516

American (AMR)

AF:

0.00144

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68006

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

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:

0.00107

Hom.:

Bravo

AF:

0.00358

ESP6500AA

AF:

0.00981

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000960

AC:

116

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000594

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0063

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.55

PhyloP100

1.9

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.16

REVEL

Benign

0.20

Sift

Benign

0.16

Sift4G

Benign

0.23

Polyphen

0.31

Vest4

0.055

MVP

0.66

MPC

0.042

ClinPred

0.011

GERP RS

2.1

Varity_R

0.028

gMVP

0.34

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over