rs147654123

chr20-36195330-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_012156.2(EPB41L1):c.1451C>T(p.Pro484Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,613,990 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (10 hom.)
• Consequence: EPB41L1 NM_012156.2 missense, splice_region
• Scores: Splicing: ADA: 0.9398
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.05

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]

LOC124904892 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EPB41L1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0068655014).
• BP6: Variant 20-36195330-C-T is Benign according to our data. Variant chr20-36195330-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 210943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-36195330-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 303 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB41L1	NM_012156.2	c.1451C>T	p.Pro484Leu	missense_variant, splice_region_variant	13/22	ENST00000338074.7
LOC124904892	XR_007067571.1	n.264+1352G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB41L1	ENST00000338074.7	c.1451C>T	p.Pro484Leu	missense_variant, splice_region_variant	13/22	1	NM_012156.2	P5

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 303 AN: 152036 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00172 AC: 433 AN: 251384 Hom.: 1 AF XY: 0.00167 AC XY: 227 AN XY: 135884

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00365 AC: 5337 AN: 1461836 Hom.: 10 Cov.: 32 AF XY: 0.00348 AC XY: 2534 AN XY: 727228

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00452

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152154 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74404

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00366

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00186

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00162 AC: 197

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	EPB41L1: BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 03, 2017

- -

EPB41L1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

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	0.082
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T;T;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.015	.;B;.
Vest4		0.25
MVP		0.29
MPC		0.23
ClinPred		0.016	T
GERP RS		5.2
Varity_R		0.090
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.010		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: rs147654123; hg19: chr20-34783252; COSMIC: COSV52442752; COSMIC: COSV52442752;