20-36173938-C-A

Variant names:

• chr20-36173938-C-A
• rs371405277
• NM_012156.2:c.161C>A

Variant summary

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

The NM_012156.2(EPB41L1):​c.161C>A​(p.Thr54Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T54M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPB41L1 NM_012156.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• 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=0.07002476).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012156.2. 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_012156.2	MANE Select	c.161C>A	p.Thr54Lys	missense	Exon 2 of 22	NP_036288.2	Q9H4G0-1
	EPB41L1	NM_001433605.1		c.161C>A	p.Thr54Lys	missense	Exon 2 of 23	NP_001420534.1
	EPB41L1	NM_001258329.1		c.161C>A	p.Thr54Lys	missense	Exon 3 of 23	NP_001245258.1	A0A0C4DH22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41L1	ENST00000338074.7	TSL:1 MANE Select	c.161C>A	p.Thr54Lys	missense	Exon 2 of 22	ENSP00000337168.2	Q9H4G0-1
	EPB41L1	ENST00000373946.7	TSL:1	c.161C>A	p.Thr54Lys	missense	Exon 3 of 23	ENSP00000363057.4	A0A0C4DH22
	EPB41L1	ENST00000202028.9	TSL:1	c.-9-1613C>A		intron	N/A	ENSP00000202028.5	Q9H4G0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461052 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726786

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111610

Other (OTH) AF: 0.0000166 AC: 1 AN: 60348

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-0.34	N
PhyloP100		2.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Benign	0.36	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.23		Gain of ubiquitination at T54 (P = 0.0011)
MVP		0.51
MPC		0.89
ClinPred		0.21	T
GERP RS		5.8
PromoterAI		0.054	Neutral
Varity_R		0.15
gMVP		0.28
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs371405277; hg19: chr20-34761860;