20-36125460-G-A

Position:

• chr20-36125460-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000373946.7(EPB41L1):​c.-15+11661G>A variant causes a intron 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: EPB41L1 ENST00000373946.7 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.290

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 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB41L1	NM_001258330.1	c.17G>A	p.Arg6Lys	missense_variant	3/21		NP_001245259.1
EPB41L1	NM_001258329.1	c.-15+11661G>A		intron_variant			NP_001245258.1
EPB41L1	NM_001258331.2	c.-10+12980G>A		intron_variant			NP_001245260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB41L1	ENST00000202028.9	c.-10+12980G>A		intron_variant		1		ENSP00000202028
EPB41L1	ENST00000373946.7	c.-15+11661G>A		intron_variant		1		ENSP00000363057	A1
EPB41L1	ENST00000628415.2	c.17G>A	p.Arg6Lys	missense_variant	3/21	2		ENSP00000487049

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000243

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

A heterozygous missense variant was identified, NM_001258330.1(EPB41L1):c.17G>A in exon 3 of the EPB41L1 gene (NB: this variant is non-coding in alternative transcripts). This substitution is predicted to create a minor amino acid change from an arginine to a lysine at position 6 of the protein; NP_001245259.1(EPB41L1):p.(Arg6Lys). The arginine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB). In silico software predictions of the pathogenicity of this variant are conflicting (SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. This variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS with LOW CLINICAL RELEVANCE. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	N;N;N;N;N
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

Splicing

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: chr20-34713382;