20-36173889-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_012156.2(EPB41L1):c.112G>A(p.Gly38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,916 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: EPB41L1 NM_012156.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.815

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EPB41L1
• BP4: Computational evidence support a benign effect (MetaRNN=0.03917876).
• BP6: Variant 20-36173889-G-A is Benign according to our data. Variant chr20-36173889-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2397829.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB41L1	NM_012156.2	c.112G>A	p.Gly38Ser	missense_variant	2/22	ENST00000338074.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB41L1	ENST00000338074.7	c.112G>A	p.Gly38Ser	missense_variant	2/22	1	NM_012156.2	P5

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000480 AC: 12 AN: 250046 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135318

Gnomad AFR exome AF: 0.000620

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727166

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74414

Gnomad4 AFR AF: 0.000578

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: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.112G>A (p.G38S) 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 112, causing the glycine (G) at amino acid position 38 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

EPB41L1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	20
Dann	Benign	0.83
DEOGEN2	Benign	0.015	T;.;T;T;T;T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;.
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.039	T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	D;D;D;D;D;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.31	N;.;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.88	T;.;T;T;.;T;T
Sift4G	Benign	0.76	T;T;T;T;T;T;T
Polyphen		0.10, 0.14	.;.;B;.;.;B;.
Vest4		0.13, 0.13, 0.16
MVP		0.72
MPC		0.73
ClinPred		0.025	T
GERP RS		3.8
Varity_R		0.057
gMVP		0.16

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

Other links and lift over

dbSNP: rs145893462; hg19: chr20-34761811; COSMIC: COSV99151240;