19-16361940-C-T

Variant names:

• chr19-16361940-C-T
• rs144312610
• NM_001258374.3:c.2425G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001258374.3(EPS15L1):​c.2425G>A​(p.Glu809Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000668 in 1,613,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: EPS15L1 NM_001258374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67
• Publications: 3 publications found

Genes affected

EPS15L1 (HGNC:24634): (epidermal growth factor receptor pathway substrate 15 like 1) Enables cadherin binding activity. Predicted to be involved in endocytosis and endosomal transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

EPS15L1 Gene-Disease associations (from GenCC):

• split hand-foot malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012489945).
• BS2: High AC in GnomAd4 at 53 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258374.3. 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
	EPS15L1	NM_001258374.3	MANE Select	c.2425G>A	p.Glu809Lys	missense	Exon 23 of 24	NP_001245303.1	Q9UBC2-2
	EPS15L1	NM_001438224.1		c.2473G>A	p.Glu825Lys	missense	Exon 24 of 25	NP_001425153.1
	EPS15L1	NM_021235.3		c.2425G>A	p.Glu809Lys	missense	Exon 23 of 23	NP_067058.1	Q9UBC2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS15L1	ENST00000455140.7	TSL:2 MANE Select	c.2425G>A	p.Glu809Lys	missense	Exon 23 of 24	ENSP00000393313.1	Q9UBC2-2
	EPS15L1	ENST00000248070.10	TSL:1	c.2425G>A	p.Glu809Lys	missense	Exon 23 of 23	ENSP00000248070.5	Q9UBC2-1
	EPS15L1	ENST00000535753.6	TSL:1	c.*27G>A		3_prime_UTR	Exon 22 of 22	ENSP00000440103.1	Q9UBC2-3

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151784 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000296 AC: 74 AN: 249914 AF XY: 0.000325

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000566

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000701 AC: 1025 AN: 1461388 Hom.: 0 Cov.: 33 AF XY: 0.000616 AC XY: 448 AN XY: 726982

African (AFR) AF: 0.000209 AC: 7 AN: 33438

American (AMR) AF: 0.000134 AC: 6 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53406

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.000865 AC: 962 AN: 1111774

Other (OTH) AF: 0.000729 AC: 44 AN: 60354

GnomAD4 genome AF: 0.000349 AC: 53 AN: 151902 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 25 AN XY: 74218

African (AFR) AF: 0.000145 AC: 6 AN: 41382

American (AMR) AF: 0.000328 AC: 5 AN: 15254

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000589 AC: 40 AN: 67954

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000455 Hom.: 0

Bravo AF: 0.000366

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000763

EpiControl AF: 0.000652

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	Benign	0.067
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Benign	0.41
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.3	N
PhyloP100		4.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.25
MVP		0.20
MPC		0.098
ClinPred		0.042	T
GERP RS		3.5
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.063
gMVP		0.20
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144312610; hg19: chr19-16472751; COSMIC: COSV105854860; COSMIC: COSV105854860;