2-120074169-A-C

Variant names:

• chr2-120074169-A-C
• rs760710287
• NM_020909.4:c.398A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020909.4(EPB41L5):​c.398A>C​(p.Glu133Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000602 in 1,610,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: EPB41L5 NM_020909.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.45
• Publications: 0 publications found

Genes affected

EPB41L5 (HGNC:19819): (erythrocyte membrane protein band 4.1 like 5) Predicted to enable cytoskeletal protein binding activity and protein domain specific binding activity. Predicted to be involved in actomyosin structure organization. Predicted to act upstream of or within several processes, including chordate embryonic development; embryonic foregut morphogenesis; and mesoderm morphogenesis. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020909.4. 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
	EPB41L5	NM_020909.4	MANE Select	c.398A>C	p.Glu133Ala	missense	Exon 5 of 25	NP_065960.2
	EPB41L5	NM_001330310.2		c.398A>C	p.Glu133Ala	missense	Exon 5 of 25	NP_001317239.1	Q9HCM4-3
	EPB41L5	NM_001184937.2		c.398A>C	p.Glu133Ala	missense	Exon 5 of 24	NP_001171866.1	Q9HCM4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41L5	ENST00000263713.10	TSL:1 MANE Select	c.398A>C	p.Glu133Ala	missense	Exon 5 of 25	ENSP00000263713.5	Q9HCM4-1
	EPB41L5	ENST00000443124.5	TSL:1	c.398A>C	p.Glu133Ala	missense	Exon 5 of 17	ENSP00000393722.1	Q9HCM4-2
	EPB41L5	ENST00000851970.1		c.398A>C	p.Glu133Ala	missense	Exon 5 of 25	ENSP00000522029.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248356 AF XY: 0.0000224

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000644 AC: 94 AN: 1458848 Hom.: 0 Cov.: 30 AF XY: 0.0000730 AC XY: 53 AN XY: 725718

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 85876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000847 AC: 94 AN: 1109974

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151984 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74230

African (AFR) AF: 0.0000242 AC: 1 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000110

EpiControl AF: 0.0000597

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.4
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.83
MPC		0.28
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.74
gMVP		0.59
Mutation Taster		=43/57	disease causing

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: rs760710287; hg19: chr2-120831745;