Genetic Variant EPB41L4A:p.Asn526Thr (chr5-112184061-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022140.5(EPB41L4A):c.1577A>C(p.Asn526Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. N526I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EPB41L4A
NM_022140.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.682

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026461035).

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.1577A>C	p.Asn526Thr	missense	Exon 18 of 23	NP_071423.4
EPB41L4A	NM_001347887.2		c.1577A>C	p.Asn526Thr	missense	Exon 18 of 24	NP_001334816.1
EPB41L4A	NR_144931.2		n.1815A>C		non_coding_transcript_exon	Exon 18 of 23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPB41L4A	ENST00000261486.6	TSL:1 MANE Select	c.1577A>C	p.Asn526Thr	missense	Exon 18 of 23	ENSP00000261486.5	Q9HCS5
EPB41L4A	ENST00000507810.5	TSL:2	n.597A>C		non_coding_transcript_exon	Exon 7 of 14
EPB41L4A	ENST00000515047.5	TSL:3	n.397A>C		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460328

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110876

Other (OTH)

AF:

0.00

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.7

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0060

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.76

M_CAP

Benign

0.0073

MetaRNN

Benign

0.026

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.095

PhyloP100

-0.68

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.67

REVEL

Benign

0.20

Sift

Benign

0.93

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.14

MutPred

0.14

Gain of phosphorylation at N526 (P = 0.023)

MVP

0.63

MPC

0.043

ClinPred

0.097

GERP RS

0.66

Varity_R

0.030

gMVP

0.33

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over