20-36175570-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_012156.2(EPB41L1):c.197A>G(p.Lys66Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPB41L1 NM_012156.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, EPB41L1
• BP4: Computational evidence support a benign effect (MetaRNN=0.17308041).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB41L1	NM_012156.2	c.197A>G	p.Lys66Arg	missense_variant	3/22	ENST00000338074.7
LOC124904892	XR_007067571.1	n.405-401T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB41L1	ENST00000338074.7	c.197A>G	p.Lys66Arg	missense_variant	3/22	1	NM_012156.2	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251482 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.197A>G (p.K66R) alteration is located in exon 3 (coding exon 2) of the EPB41L1 gene. This alteration results from a A to G substitution at nucleotide position 197, causing the lysine (K) at amino acid position 66 to be replaced by an arginine (R). 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	0.093
BayesDel_addAF	Benign	-0.000079	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	0.95	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.96	N;D;N;N;N;N;.;.;N;N;N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.014	D;D;T;T;T;D;.;.;T;T;T;T;T
Sift4G	Benign	0.56	T;D;T;T;T;T;T;T;T;D;T;T;T
Polyphen		0.86	P;.;.;.;P;P;.;D;P;.;.;D;.
Vest4		0.36
MutPred		0.16		.;.;Loss of ubiquitination at K66 (P = 8e-04);.;.;.;Loss of ubiquitination at K66 (P = 8e-04);.;Loss of ubiquitination at K66 (P = 8e-04);Loss of ubiquitination at K66 (P = 8e-04);.;Loss of ubiquitination at K66 (P = 8e-04);Loss of ubiquitination at K66 (P = 8e-04);
MVP		0.67
MPC		1.1
ClinPred		0.82	D
GERP RS		5.8
Varity_R		0.074
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: rs1203146357; hg19: chr20-34763492;