19-55080773-C-A

Variant names:

• chr19-55080773-C-A
• rs201364329
• NM_133180.3:c.431C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_133180.3(EPS8L1):​c.431C>A​(p.Ala144Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. A144V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EPS8L1 NM_133180.3 missense, splice_region
• Scores: Splicing: ADA: 0.03877
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 3 publications found

Genes affected

EPS8L1 (HGNC:21295): (EPS8 signaling adaptor L1) This gene encodes a protein that is related to epidermal growth factor receptor pathway substrate 8 (EPS8), a substrate for the epidermal growth factor receptor. The function of this protein is unknown. At least two alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133180.3. 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
	EPS8L1	NM_133180.3	MANE Select	c.431C>A	p.Ala144Glu	missense splice_region	Exon 7 of 20	NP_573441.2	Q8TE68-1
	EPS8L1	NM_017729.4		c.50C>A	p.Ala17Glu	missense splice_region	Exon 2 of 15	NP_060199.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8L1	ENST00000201647.11	TSL:1 MANE Select	c.431C>A	p.Ala144Glu	missense splice_region	Exon 7 of 20	ENSP00000201647.5	Q8TE68-1
	EPS8L1	ENST00000245618.5	TSL:1	c.50C>A	p.Ala17Glu	missense splice_region	Exon 2 of 15	ENSP00000245618.4	Q8TE68-2
	EPS8L1	ENST00000587786.5	TSL:1	n.317C>A		splice_region non_coding_transcript_exon	Exon 5 of 14	ENSP00000465830.1	K7EKX9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000461 AC: 1 AN: 216734 AF XY: 0.00

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: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444810 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 717686

African (AFR) AF: 0.00 AC: 0 AN: 32890

American (AMR) AF: 0.00 AC: 0 AN: 41150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38216

South Asian (SAS) AF: 0.00 AC: 0 AN: 84888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105718

Other (OTH) AF: 0.00 AC: 0 AN: 59730

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000834 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.82		Gain of disorder (P = 0.0315)
MVP		0.66
MPC		1.0
ClinPred		1.0	D
GERP RS		2.6
PromoterAI		-0.074	Neutral
Varity_R		0.79
gMVP		0.86
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.039
dbscSNV1_RF	Benign	0.25
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 2

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

Other links and lift over

dbSNP: rs201364329; hg19: chr19-55592141;