chr9-109176606-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_019114.5(EPB41L4B):​c.2578G>A​(p.Val860Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

EPB41L4B
NM_019114.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0860
Variant links:
Genes affected
EPB41L4B (HGNC:19818): (erythrocyte membrane protein band 4.1 like 4B) Predicted to be a structural constituent of cytoskeleton. Involved in several processes, including positive regulation of cell adhesion; positive regulation of keratinocyte migration; and wound healing. Acts upstream of or within actomyosin structure organization. Located in apical part of cell; cytosol; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03153482).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EPB41L4BNM_019114.5 linkc.2578G>A p.Val860Ile missense_variant Exon 25 of 26 ENST00000374566.8 NP_061987.3 Q9H329-1Q59GC2Q9NSG9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EPB41L4BENST00000374566.8 linkc.2578G>A p.Val860Ile missense_variant Exon 25 of 26 1 NM_019114.5 ENSP00000363694.3 Q9H329-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249416
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135316
show subpopulations
Gnomad AFR exome
AF:
0.000129
Gnomad AMR exome
AF:
0.00
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:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461772
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
10
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000340
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000255
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2578G>A (p.V860I) alteration is located in exon 25 (coding exon 25) of the EPB41L4B gene. This alteration results from a G to A substitution at nucleotide position 2578, causing the valine (V) at amino acid position 860 to be replaced by an isoleucine (I). 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
-0.36
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
12
DANN
Benign
0.94
DEOGEN2
Benign
0.016
T
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.026
N
LIST_S2
Benign
0.48
T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.032
T
MetaSVM
Benign
-0.73
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.20
N
REVEL
Benign
0.15
Sift
Benign
0.17
T
Sift4G
Benign
0.32
T
Polyphen
0.010
B
Vest4
0.045
MVP
0.19
MPC
0.20
ClinPred
0.058
T
GERP RS
1.5
Varity_R
0.032
gMVP
0.089

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

LitVar

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

Other links and lift over

dbSNP: rs368177192; hg19: chr9-111938886; COSMIC: COSV65804868; API