chr20-36125460-G-A

Variant names:

• chr20-36125460-G-A
• ENST00000373946.7:c.-15+11661G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001258330.1(EPB41L1):​c.17G>A​(p.Arg6Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000115 in 870,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 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)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: EPB41L1 NM_001258330.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.290
• Publications: 0 publications found

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]

EPB41L1 Gene-Disease associations (from GenCC):

• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• intellectual disability, autosomal dominant 11

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070534766).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258330.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41L1	NM_001258330.1		c.17G>A	p.Arg6Lys	missense	Exon 3 of 21	NP_001245259.1	B7Z653
	EPB41L1	NM_001258329.1		c.-15+11661G>A		intron	N/A	NP_001245258.1	A0A0C4DH22
	EPB41L1	NM_001424407.1		c.-10+12980G>A		intron	N/A	NP_001411336.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41L1	ENST00000373946.7	TSL:1	c.-15+11661G>A		intron	N/A	ENSP00000363057.4	A0A0C4DH22
	EPB41L1	ENST00000202028.9	TSL:1	c.-10+12980G>A		intron	N/A	ENSP00000202028.5	Q9H4G0-2
	EPB41L1	ENST00000628415.2	TSL:2	c.17G>A	p.Arg6Lys	missense	Exon 3 of 21	ENSP00000487049.2	Q9H4G0-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000115 AC: 1 AN: 870612 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 449528

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21696

American (AMR) AF: 0.00 AC: 0 AN: 35078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22016

East Asian (EAS) AF: 0.00 AC: 0 AN: 33458

South Asian (SAS) AF: 0.00 AC: 0 AN: 69124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 609960

Other (OTH) AF: 0.0000243 AC: 1 AN: 41088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, autosomal dominant 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Benign	-0.97
CADD	Benign	6.8
DANN	Benign	0.70
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.89	T
PhyloP100		-0.29
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.38		Gain of ubiquitination at R6 (P = 0.0131)
GERP RS		-4.8
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr20-34713382;