chr20-36173906-C-G

Position:

• chr20-36173906-C-G

Variant summary

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

The ENST00000338074.7(EPB41L1):​c.129C>G​(p.Asn43Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: EPB41L1 ENST00000338074.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.459

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.13147622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB41L1	NM_012156.2	c.129C>G	p.Asn43Lys	missense_variant	2/22	ENST00000338074.7	NP_036288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB41L1	ENST00000338074.7	c.129C>G	p.Asn43Lys	missense_variant	2/22	1	NM_012156.2	ENSP00000337168	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Aug 26, 2022

The c.129C>G (p.N43K) alteration is located in exon 2 (coding exon 1) of the EPB41L1 gene. This alteration results from a C to G substitution at nucleotide position 129, causing the asparagine (N) at amino acid position 43 to be replaced by a lysine (K). 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	0.16
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.021	T;.;T;T;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0021
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;.
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.41	.;.;.;.;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N;.;N;N;D;N;N
REVEL	Benign	0.13
Sift	Benign	0.67	T;.;T;D;.;T;T
Sift4G	Benign	0.84	T;T;T;T;T;T;T
Polyphen		0.14, 0.15	.;.;B;.;.;B;.
Vest4		0.18, 0.14, 0.17
MutPred		0.26		Gain of ubiquitination at N43 (P = 9e-04);Gain of ubiquitination at N43 (P = 9e-04);Gain of ubiquitination at N43 (P = 9e-04);Gain of ubiquitination at N43 (P = 9e-04);Gain of ubiquitination at N43 (P = 9e-04);Gain of ubiquitination at N43 (P = 9e-04);Gain of ubiquitination at N43 (P = 9e-04);
MVP		0.71
MPC		0.86
ClinPred		0.18	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-34761828;