20-36173856-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_012156.2(EPB41L1):​c.79G>A​(p.Ala27Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

EPB41L1
NM_012156.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0580
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EPB41L1. . Gene score misZ 1.9386 (greater than the threshold 3.09). Trascript score misZ 4.2392 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder.
BP4
Computational evidence support a benign effect (MetaRNN=0.086657286).
BS2
High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EPB41L1NM_012156.2 linkuse as main transcriptc.79G>A p.Ala27Thr missense_variant 2/22 ENST00000338074.7 NP_036288.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EPB41L1ENST00000338074.7 linkuse as main transcriptc.79G>A p.Ala27Thr missense_variant 2/221 NM_012156.2 ENSP00000337168 P5Q9H4G0-1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248776
Hom.:
0
AF XY:
0.00000742
AC XY:
1
AN XY:
134848
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000363
AC:
53
AN:
1461658
Hom.:
0
Cov.:
32
AF XY:
0.0000344
AC XY:
25
AN XY:
727132
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000405
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.0000808
AC XY:
6
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 19, 2024The c.79G>A (p.A27T) alteration is located in exon 2 (coding exon 1) of the EPB41L1 gene. This alteration results from a G to A substitution at nucleotide position 79, causing the alanine (A) at amino acid position 27 to be replaced by a threonine (T). 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
0.065
BayesDel_addAF
Benign
-0.066
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
13
DANN
Uncertain
0.99
DEOGEN2
Benign
0.021
T;.;T;T;T;T;.
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.81
T;T;T;T;T;T;.
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.087
T;T;T;T;T;T;T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
1.0
.;.;.;.;.;L;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.6
N;.;N;N;D;N;N
REVEL
Benign
0.26
Sift
Benign
0.30
T;.;T;T;.;T;T
Sift4G
Benign
0.20
T;T;T;T;T;T;T
Polyphen
0.0, 0.48
.;.;B;.;.;P;.
Vest4
0.12, 0.14, 0.11
MutPred
0.18
Gain of glycosylation at A27 (P = 0.002);Gain of glycosylation at A27 (P = 0.002);Gain of glycosylation at A27 (P = 0.002);Gain of glycosylation at A27 (P = 0.002);Gain of glycosylation at A27 (P = 0.002);Gain of glycosylation at A27 (P = 0.002);Gain of glycosylation at A27 (P = 0.002);
MVP
0.76
MPC
0.71
ClinPred
0.098
T
GERP RS
4.6
Varity_R
0.051
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs111421912; hg19: chr20-34761778; COSMIC: COSV52438227; API